Novel Heterocyclic Compounds as Bromodomain Inhibitors

ABSTRACT

The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.

This patent application claims the benefit of priority under 35 U.S.C.§120 to U.S. Provisional Application No. 61/745,274, filed on Dec. 21,2012, the entirety of which is incorporated herein by reference.

The present disclosure relates to novel compounds, pharmaceuticalcompositions containing such compounds, and their use in prevention andtreatment of diseases and conditions.

Post-translational modifications (PTMs) of histones are involved inregulation of gene expression and chromatin organization in eukaryoticcells. Histone acetylation at specific lysine residues is a PTM that isregulated by histone acetylases (HATs) and deacetylases (HDACs) [1].Small molecule inhibitors of HDACs and HATs are being investigated ascancer therapy [2-5]. Histone acetylation controls gene expression byrecruiting protein complexes that bind directly to acetylated lysine viabromodomains [6]. One such family, the bromodomain and extra terminaldomain (BET) proteins, comprises Brd2, Brd3, Brd4, and BrdT, each ofwhich contains two bromodomains in tandem that can independently bind toacetylated lysines, as reviewed in [7].

Interfering with BET protein interactions via bromodomain inhibitionresults in modulation of transcriptional programs that are oftenassociated with diseases characterized by dysregulation of cell cyclecontrol, inflammatory cytokine expression, viral transcription,hematopoietic differentiation, insulin transcription, and adipogenesis[8].

BET inhibitors are believed to be useful in the treatment of diseases orconditions related to systemic or tissue inflammation, inflammatoryresponses to infection or hypoxia, cellular activation andproliferation, lipid metabolism, fibrosis, and the prevention andtreatment of viral infections [8, 9].

Autoimmune diseases, which are often chronic and debilitating, are aresult of a dysregulated immune response, which leads the body to attackits own cells, tissues, and organs. Pro-inflammatory cytokines includingIL-1β, TNF-α, IL-6, MCP-1, and IL-17 are overexpressed in autoimmunedisease. IL-17 expression defines the T cell subset known as Th17 cells,which are differentiated, in part, by IL-6, and drive many of thepathogenic consequences of autoimmune disease. Thus, the IL-6/Th17 axisrepresents an important, potentially druggable target in autoimmunedisease therapy [10].

BET inhibitors are expected to have anti-inflammatory andimmunomodulatory properties [8, 9]. BET inhibitors have been shown tohave a broad spectrum of anti-inflammatory effects in vitro includingthe ability to decrease expression of pro-inflammatory cytokines such asIL-1β, MCP-1, TNF-α, and IL-6 in activated immune cells [11-13]. Themechanism for these anti-inflammatory effects may involve BET inhibitordisruption of Brd4 co-activation of NF-κB-regulated pro-inflammatorycytokines and/or displacement of BET proteins from cytokine promoters,including IL-6 [12, 14, 15]. In addition, because Brd4 is involved inT-cell lineage differentiation, BET inhibitors may be useful ininflammatory disorders characterized by specific programs of T celldifferentiation [16].

The anti-inflammatory and immunomodulatory effects of BET inhibitionhave also been confirmed in vivo. A BET inhibitor prevented endotoxin-or bacterial sepsis-induced death and cecal ligation puncture-induceddeath in mice, suggesting utility for BET inhibitors in sepsis and acuteinflammatory disorders [12]. A BET inhibitor has been shown toameliorate inflammation and kidney injury in HIV-1 transgenic mice, ananimal model for HIV-associated nephropathy, in part through inhibitionof Brd4 interaction with NF-κB [14]. The utility of BET inhibition inautoimmune disease was demonstrated in a mouse model of multiplesclerosis, where BET inhibition resulted in abrogation of clinical signsof disease, in part, through inhibition of IL-6 and IL-17 [17]. Theseresults were supported in a similar mouse model where it was shown thattreatment with a BET inhibitor inhibited T cell differentiation intopro-autoimmune Th1 and Th17 subsets in vitro, and further abrogateddisease induction by pro-inflammatory Th1 cells [18].

BET inhibitors may be useful in the treatment of a variety of chronicautoimmune inflammatory conditions. Examples of autoimmune andinflammatory diseases, disorders, and syndromes that may be treatedusing the compounds and methods include but are not limited to,inflammatory pelvic disease, urethritis, skin sunburn, sinusitis,pneumonitis, encephalitis, meningitis, myocarditis, nephritis [14],osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis,gingivitis, appendicitis, pancreatitis, cholecystitis,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis [9], Sjogren's disease, tissue graftrejection, hyperacute rejection of transplanted organs, asthma, allergicrhinitis, chronic obstructive pulmonary disease (COPD), autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),autoimmune alopecia, pernicious anemia, glomerulonephritis,dermatomyositis, multiple sclerosis [18], scleroderma, vasculitis,autoimmune hemolytic and thrombocytopenic states, Goodpasture'ssyndrome, atherosclerosis, Addison's disease, Parkinson's disease,Alzheimer's disease, Type I diabetes [8], septic shock [12], systemiclupus erythematosus (SLE) [9], rheumatoid arthritis [19], psoriaticarthritis, juvenile arthritis, osteoarthritis, chronic idiopathicthrombocytopenic purpura, Waldenstrom macroglobulinemia, myastheniagravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative jointdisease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome,Behcet's disease, uveitis, dry eye disease, scleroderma, mycosisfungoides, and Graves' disease.

BET inhibitors may be useful in the treatment of a wide variety of acuteinflammatory conditions including but not limited to, acute gout, giantcell arteritis, nephritis including lupus nephritis, vasculitis withorgan involvement, such as glomerulonephritis, vasculitis, includinggiant cell arteritis, Wegener's granulomatosis, polyarteritis nodosa,Behcet's disease, Kawasaki disease, and Takayasu's arteritis.

BET inhibitors may be useful in the prevention and treatment of diseasesor conditions that involve inflammatory responses to infections withbacteria, viruses, fungi, parasites, and their toxins, such as, but notlimited to sepsis, sepsis syndrome, septic shock [12], systemicinflammatory response syndrome (SIRS), multi-organ dysfunction syndrome,toxic shock syndrome, acute lung injury, adult respiratory distresssyndrome (ARDS), acute renal failure, fulminant hepatitis, burns,post-surgical syndromes, sarcoidosis, Herxheimer reactions,encephalitis, myelitis, meningitis, malaria, and SIRS associated withviral infections, such as influenza, herpes zoster, herpes simplex, andcoronavirus [8].

Cancer is a group of diseases caused by dysregulated cell proliferation.Therapeutic approaches aim to decrease the numbers of cancer cells byinhibiting cell replication or by inducing cancer cell differentiationor death, but there is still significant unmet medical need for moreefficacious therapeutic agents. Cancer cells accumulate genetic andepigenetic changes that alter cell growth and metabolism, promoting cellproliferation and increasing resistance to programmed cell death, orapoptosis. Some of these changes include inactivation of tumorsuppressor genes, activation of oncogenes, and modifications of theregulation of chromatin structure, including deregulation of histonePTMs [20, 21].

The present disclosure provides a method for treating human cancer,including, but not limited to, cancers that result from aberranttranslocation or overexpression of BET proteins (e.g., NUT midlinecarcinoma (NMC) [22]) and B-cell lymphoma [23]). NMC tumor cell growthis driven by a translocation of the Brd4 or Brd3 gene to the nutlin 1gene [24]. BET inhibition has demonstrated potent antitumor activity inmurine xenograft models of NMC, a rare but lethal form of cancer [24].

The present disclosure provides a method for treating human cancers,including, but not limited to, cancers dependent on a member of the mycfamily of oncoproteins including c-myc, MYCN, and L-myc [25]. Thesecancers include Burkitt's lymphoma, acute myelogenous leukemia, multiplemyeloma, and aggressive human medulloblastoma [25]. Cancers in whichc-myc is overexpressed may be particularly susceptible to BET proteininhibition; it has been shown that treatment of tumors that haveactivation of c-myc with a BET inhibitor resulted in tumor regressionthrough inactivation of c-myc transcription [26-30].

The present disclosure provides a method for treating human cancersincluding cancers that rely on BET proteins and pTEFb (Cdk9/CyclinT) toregulate oncogenes [31], and cancers that can be treated by inducingapoptosis or senescence by inhibiting Bcl2, cyclin-dependent kinase 6(CDK6) [26], or human telomerase reverse transcriptase (hTERT) [27, 32].

BET inhibitors may be useful in the treatment of cancers including, butnot limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma,acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia,acute erythroid leukemia, acute lymphoblastic leukemia, acutemegakaryoblastic leukemia, acute monocytic leukemia, acute myeloidleukemia [26, 28, 30], adenocarcinoma, adenoid cystic carcinoma,adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adiposetissue neoplasm, adrenocortical carcinoma, adult T-cellleukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma,alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblasticfibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer,angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma,astrocytoma, atypical teratoid rhabdoid tumor, B-cell acutelymphoblastic leukemia [29], B-cell chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, B-cell lymphoma [23], basal cell carcinoma,biliary tract cancer, bladder cancer, blastoma, bone cancer, Brennertumor, Brown tumor, Burkitt's lymphoma [28], breast cancer, braincancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor,cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma,choroid plexus papilloma, clear-cell sarcoma of the kidney,craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer,colorectal cancer, Degos disease, desmoplastic small round cell tumor,diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor,dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermalsinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer,fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicularthyroid cancer, ganglioneuroma, gastrointestinal cancer, germ celltumor, gestational choriocarcinoma, giant cell fibroblastoma, giant celltumor of the bone, glial tumor, glioblastoma multiforme, glioma,gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia [28], chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma [33], meningioma,Merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mixed lineage leukemia [26], mucinous tumor, multiplemyeloma [27], muscle tissue neoplasm, mycosis fungoides, myxoidliposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma,neuroblastoma, neurofibroma, neuroma, nodular melanoma, NUT-midlinecarcinoma [24], ocular cancer, oligoastrocytoma, oligodendroglioma,oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oralcancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroidcancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma,pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma,precursor T-lymphoblastic lymphoma, primary central nervous systemlymphoma, primary effusion lymphoma, primary peritoneal cancer, prostatecancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei,renal cell carcinoma, renal medullary carcinoma, retinoblastoma,rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer,sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadalstromal tumor, signet ring cell carcinoma, skin cancer, small blue roundcell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma,soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cellcarcinoma, synovial sarcoma, Sezary's disease, small intestine cancer,squamous carcinoma, stomach cancer, testicular cancer, thecoma, thyroidcancer, transitional cell carcinoma, throat cancer, urachal cancer,urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer,verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginalcancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms'tumor.

BET inhibitors may be useful in the treatment of benign proliferativeand fibrotic disorders, including benign soft tissue tumors, bonetumors, brain and spinal tumors, eyelid and orbital tumors, granuloma,lipoma, meningioma, multiple endocrine neoplasia, nasal polyps,pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheickeratoses, stomach polyps, thyroid nodules, cystic neoplasms of thepancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castlemandisease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenicgranuloma, juvenile polyposis syndrome, idiopathic pulmonary fibrosis,renal fibrosis, post-operative stricture, keloid formation, scleroderma,and cardiac fibrosis.

Cardiovascular disease (CVD) is the leading cause of mortality andmorbidity in the United States [34]. Atherosclerosis, an underlyingcause of CVD, is a multifactorial disease characterized by dyslipidemiaand inflammation. BET inhibitors are expected to be efficacious inatherosclerosis and associated conditions because of aforementionedanti-inflammatory effects as well as ability to increase transcriptionof ApoA-I, the major constituent of HDL [11, 35].

Up-regulation of ApoA-I is considered to be a useful strategy intreatment of atherosclerosis and CVD [36]. BET inhibitors have beenshown to increase ApoA-I transcription and protein expression [11, 35].It has also been shown that BET inhibitors bind directly to BET proteinsand inhibit their binding to acetylated histones at the ApoA-1 promoter,suggesting the presence of a BET protein repression complex on theApoA-1 promoter, which can be functionally disrupted by BET inhibitors.It follows that, BET inhibitors may be useful in the treatment ofdisorders of lipid metabolism via the regulation of ApoA-I and HDL suchas hypercholesterolemia, dyslipidemia, atherosclerosis [36], andAlzheimer's disease and other neurological disorders [37].

BET inhibitors may be useful in the prevention and treatment ofconditions associated with ischemia-reperfusion injury such as, but notlimited to, myocardial infarction, stroke, acute coronary syndromes [9],renal reperfusion injury, organ transplantation, coronary artery bypassgrafting, cardio-pulmonary bypass procedures, hypertension, pulmonary,renal, hepatic, gastro-intestinal, or peripheral limb embolism.

Obesity-associated inflammation is a hallmark of type II diabetes,insulin resistance, and other metabolic disorders [8, 19]. Consistentwith the ability of BET inhibitors to inhibit inflammation, genedisruption of Brd2 in mice ablates inflammation and protects animalsfrom obesity-induced insulin resistance [38]. It has been shown thatBrd2 interacts with PPARy and opposes its transcriptional function.Knockdown of Brd2 in vitro promotes transcription of PPARy-regulatednetworks, including those controlling adipogenesis [39]. In additionBrd2 is highly expressed in pancreatic 13-cells and regulatesproliferation and insulin transcription [38]. Taken together, thecombined effects of BET inhibitors on inflammation and metabolismdecrease insulin resistance and may be useful in the treatment ofpre-diabetic and type II diabetic individuals as well as patients withother metabolic complications [8].

Host-encoded BET proteins have been shown to be important fortranscriptional activation and repression of viral promoters. Brd4interacts with the E2 protein of human papilloma virus (HPV) to enableE2 mediated transcription of E2-target genes [40]. Similarly, Brd2,Brd3, and Brd4 all bind to latent nuclear antigen 1 (LANA1), encoded byKaposi's sarcoma-associated herpes virus (KSHV), promotingLANA1-dependent proliferation of KSHV-infected cells [41]. A BETinhibitor has been shown to inhibit the Brd4-mediated recruitment of thetranscription elongation complex pTEFb to the Epstein-Barr virus (EBV)viral C promoter, suggesting therapeutic value for EBV-associatedmalignancies [42]. Also, a BET inhibitor reactivated HIV in models oflatent T cell infection and latent monocyte infection, potentiallyallowing for viral eradication by complementary anti-retroviral therapy[43-46].

BET inhibitors may be useful in the prevention and treatment ofepisome-based DNA viruses including, but not limited to, humanpapillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiencyvirus [8], adenovirus, poxvirus, hepatitis B virus, and hepatitis Cvirus.

Some central nervous system (CNS) diseases are characterized bydisorders in epigenetic processes. Brd2 haplo-insufficiency has beenlinked to neuronal deficits and epilepsy [47]. SNPs in variousbromodomain-containing proteins have also been linked to mentaldisorders including schizophrenia and bipolar disorders [9]. Inaddition, the ability of BET inhibitors to increase ApoA-I transcriptionmay make BET inhibitors useful in Alzheimer's disease therapyconsidering the suggested relationship between increased ApoA-I andAlzheimer's disease and other neurological disorders [37].

BRDT is the testis-specific member of the BET protein family which isessential for chromatin remodeling during spermatogenesis [48, 49].Genetic depletion of BRDT or inhibition of BRDT interaction withacetylated histones by a BET inhibitor resulted in a contraceptiveeffect in mice, which was reversible when small molecule BET inhibitorswere used [50, 51]. These data suggest potential utility of BETinhibitors as a novel and efficacious approach to male contraception.

Monocyte chemotactic protein-1 (MCP-1, CCL2) plays an important role incardiovascular disease [52]. MCP-1, by its chemotactic activity,regulates recruitment of monocytes from the arterial lumen to thesubendothelial space, where they develop into macrophage foam cells, andinitiate the formation of fatty streaks which can develop intoatherosclerotic plaque [53]. The critical role of MCP-1 (and its cognatereceptor CCR2) in the development of atherosclerosis has been examinedin various transgenic and knockout mouse models on a hyperlipidemicbackground [54-57]. These reports demonstrate that abrogation of MCP-1signaling results in decreased macrophage infiltration to the arterialwall and decreased atherosclerotic lesion development.

The association between MCP-1 and cardiovascular disease in humans iswell-established [52]. MCP-1 and its receptor are overexpressed byendothelial cells, smooth muscle cells, and infiltratingmonocytes/macrophages in human atherosclerotic plaque [58]. Moreover,elevated circulating levels of MCP-1 are positively correlated with mostcardiovascular risk factors, measures of coronary atherosclerosisburden, and the incidence of coronary heart disease (CHD) [59]. CHDpatients with among the highest levels of MCP-1 are those with acutecoronary syndrome (ACS) [60]. In addition to playing a role in theunderlying inflammation associated with CHD, MCP-1 has been shown to beinvolved in plaque rupture, ischemic/reperfusion injury, restenosis, andheart transplant rejection [52].

MCP-1 also promotes tissue inflammation associated with autoimmunediseases including rheumatoid arthritis (RA) and multiple sclerosis(MS). MCP-1 plays a role in the infiltration of macrophages andlymphocytes into the joint in RA, and is overexpressed in the synovialfluid of RA patients [61]. Blockade of MCP-1 and MCP-1 signaling inanimal models of RA have also shown the importance of MCP-1 tomacrophage accumulation and proinflammatory cytokine expressionassociated with RA [62-65].

Overexpression of MCP-1, in the brain, cerebrospinal fluid (CSF), andblood, has also been associated with chronic and acute MS in humans[66]. MCP-1 is overexpressed by a variety of cell types in the brainduring disease progression and contributes to the infiltration ofmacrophages and lymphocytes which mediate the tissue damage associatedwith MS [66]. Genetic depletion of MCP-1 or CCR2 in the experimentalautoimmune encephalomyelitis (EAE) mouse model, a model resembling humanMS, results in resistance to disease, primarily because of decreasedmacrophage infiltration to the CNS [67, 68].

Preclinical data have suggested that small- and large-moleculeinhibitors of MCP-1 and CCR2 have potential as therapeutic agents ininflammatory and autoimmune indications.

The present disclosure includes compounds that are useful for inhibitionof BET protein function by binding to bromodomains, and their use in thetreatment and prevention of diseases and conditions, including, but notlimited to, cancer, autoimmune, and cardiovascular diseases.

The first aspect of the present disclosure includes compounds of FormulaI and methods of administering a therapeutically effective amount ofthose compounds to a mammal (e.g., a human) in need thereof.

The present invention includes compounds that are useful for inhibitionof BET protein function by binding to bromodomains, and their use in thetreatment and prevention of diseases and conditions, including, but notlimited to, cancer, autoimmune, and cardiovascular diseases.

The first aspect of the invention includes compounds of Formula I andmethods of administering a therapeutically effective amount of thosecompounds to a mammal (e.g., a human) in need thereof:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof,wherein:

-   -   W₁ is selected from N and CR₅;    -   W₂ is selected from N and CR₄;    -   W₃ is selected from N and CR₃;    -   each W may be the same or different from each other;    -   R₁ is selected from a carbocycles or heterocycles;    -   R₂ is selected from a 5- or 6-membered monocyclic carbocycle or        a 5- or 6-membered monocyclic heterocycle;    -   R₃, R₄, and R₅ are each independently selected from hydrogen,        alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, carbonate, amino, amide, halogen,        carbocycle, heterocycle, sulfone, sulfoxide, sulfide,        sulfonamide, and —CN;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle;    -   R₄ may be connected to B or R₂ to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—;    -   R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone, and        sulfoxide, carbocycle, heterocycle, or two substituents selected        from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may form an oxo        or thio-oxo group, or two substituents selected from R_(x),        R_(y), R_(z), R_(v), R₅, and R₁ may be connected in a 5- or        6-membered ring to form a bicyclic carbocycle or bicyclic        heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent and        R₂ is connected directly to the center ring;    -   R_(a), R_(b), R_(c), and R_(d) are each independently selected        from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

In another aspect of the invention, a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable carriers,diluents or excipients is provided.

In yet another aspect of the invention there is provided a compound ofFormula I, or a pharmaceutically acceptable salt thereof for use intherapy, in particular in the treatment of diseases or conditions forwhich a bromodomain inhibitor is indicated.

In yet another aspect of the invention there is provided a compound ofFormula I, or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of diseases or conditionsfor which a bromodomain inhibitor is indicated.

DEFINITIONS

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout.

As used herein, “cardiovascular disease” refers to diseases, disordersand conditions of the heart and circulatory system that are mediated byBET inhibition. Exemplary cardiovascular diseases, includingcholesterol- or lipid-related disorders, include, but are not limitedto, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis,carotid atherosclerosis, cerebrovascular disease, cerebral infarction,congestive heart failure, congenital heart disease, coronary heartdisease, coronary artery disease, coronary plaque stabilization,dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familialhypercholesterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, and lipoprotein abnormalitiesassociated with Alzheimer's disease, obesity, diabetes mellitus,syndrome X, impotence, multiple sclerosis, Parkinson's disease, andinflammatory diseases.

As used herein, “inflammatory diseases” refers to diseases, disorders,and conditions that are mediated by BET inhibition. Exemplaryinflammatory diseases, include, but are not limited to, arthritis,asthma, dermatitis, psoriasis, cystic fibrosis, post transplantationlate and chronic solid organ rejection, multiple sclerosis, systemiclupus erythematosus, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury,post-angioplasty restenosis, chronic obstructive pulmonary disease(COPD), glomerulonephritis, Graves disease, gastrointestinal allergies,conjunctivitis, atherosclerosis, coronary artery disease, angina, andsmall artery disease.

As used herein, “cancer” refers to diseases, disorders, and conditionsthat are mediated by BET inhibition. Exemplary cancers, include, but arenot limited to, chronic lymphocytic leukemia and multiple myeloma,follicular lymphoma, diffuse large B cell lymphoma with germinal centerphenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomasand activated, anaplastic large cell lymphoma, neuroblastoma and primaryneuroectodermal tumor, rhabdomyosarcoma, prostate cancer, breast cancer,NMC(NUT-midline carcinoma), acute myeloid leukemia (AML), acute Blymphoblastic leukemia (B-ALL), Burkitt's Lymphoma, B-cell lymphoma,melanoma, mixed lineage leukemia, multiple myeloma, pro-myelocyticleukemia (PML), non-Hodgkin's lymphoma, neuroblastoma, medulloblastoma,lung carcinoma (NSCLC, SCLC), and colon carcinoma.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder. For example, treating acholesterol disorder may comprise decreasing blood cholesterol levels.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which is does not. For example, “optionally substituted aryl”encompasses both “aryl” and “substituted aryl” as defined below. It willbe understood by those skilled in the art, with respect to any groupcontaining one or more substituents, that such groups are not intendedto introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

As used herein, the term “hydrate” refers to a crystal form with eithera stoichiometric or non-stoichiometric amount of water is incorporatedinto the crystal structure.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkenyl. Exemplary alkenyl groups include, but are not limitedto, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-8carbon atoms, referred to herein as (C₁-C₈)alkoxy. Exemplary alkoxygroups include, but are not limited to methoxy and ethoxy.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-8 carbonatoms, referred to herein as (C₁-C₈)alkyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, andoctyl.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-8 carbon atoms, referred to hereinas (C₂-C₈)alkynyl. Exemplary alkynyl groups include, but are not limitedto, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

The term “amide” as used herein refers to the form —NR_(a)C(O)(R_(b))—or —C(O)NR_(b)R_(c), wherein R_(a), R_(b) and R_(c) are eachindependently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amidecan be attached to another group through the carbon, the nitrogen,R_(b), or R_(c). The amide also may be cyclic, for example R_(b) andR_(c), may be joined to form a 3- to 8-membered ring, such as 5- or6-membered ring. The term “amide” encompasses groups such assulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versionsthereof. The term “amide” also encompasses an amide group attached to acarboxy group, e.g., -amide-COOH or salts such as -amide-COONa, an aminogroup attached to a carboxy group (e.g., -amino-COOH or salts such as-amino-COONa).

The term “amine” or “amino” as used herein refers to the form—NR_(d)R_(e) or —N(R_(d))R_(e)—, where R_(d) and R_(e) are independentlyselected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The aminocan be attached to the parent molecular group through the nitrogen. Theamino also may be cyclic, for example any two of R_(d) and R_(e) may bejoined together or with the N to form a 3- to 12-membered ring (e.g.,morpholino or piperidinyl). The term amino also includes thecorresponding quaternary ammonium salt of any amino group. Exemplaryamino groups include alkylamino groups, wherein at least one of R_(d) orR_(e) is an alkyl group. In some embodiments Rd and Re each may beoptionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system. The aryl group can optionallybe fused to one or more rings selected from aryls, cycloalkyls, andheterocyclyls. The aryl groups of this present disclosure can besubstituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary arylgroups include, but are not limited to, phenyl, tolyl, anthracenyl,fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fusedcarbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary arylgroups also include, but are not limited to a monocyclic aromatic ringsystem, wherein the ring comprises 6 carbon atoms, referred to herein as“(C₆)aryl.”

The term “arylalkyl” as used herein refers to an alkyl group having atleast one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.”

The term “carbamate” as used herein refers to the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include,but are not limited to, arylcarbamates or heteroaryl carbamates (e.g.,wherein at least one of R_(g), R_(h) and R_(i) are independentlyselected from aryl or heteroaryl, such as pyridine, pyridazine,pyrimidine, and pyrazine).

The term “carboxy” as used herein refers to —COON or its correspondingcarboxylate salts (e.g., —COONa). The term carboxy also includes“carboxycarbonyl,” e.g. a carboxy group attached to a carbonyl group,e.g., —C(O)—COOH or salts, such as —C(O)—COONa.

The term “cyano” as used herein refers to —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-12 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl saturated orunsaturated, aryl, or heterocyclyl groups.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids may besubstituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include,but are not limited to succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid,aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malicacid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides (for example, succinic anhydrideand succinimide).

The term “ester” refers to the structure —C(O)O—, —C(O)O—R_(j-),—R_(k)C(O)O—R_(j-), or —R_(k)C(O)O—, where O is not bound to hydrogen,and R_(j) and R_(k) can independently be selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl,ether, haloalkyl, heteroaryl, and heterocyclyl. R_(k) can be a hydrogen,but R_(j) cannot be hydrogen. The ester may be cyclic, for example thecarbon atom and R_(j), the oxygen atom and R_(k), or R_(j) and R_(k) maybe joined to form a 3- to 12-membered ring. Exemplary esters include,but are not limited to, alkyl esters wherein at least one of Rj or Rk isalkyl, such as —O—C(O)-alkyl, —C(O)—O-alkyl-, and -alkyl-C(O)—O-alkyl-.Exemplary esters also include aryl or heteoraryl esters, e.g. wherein atleast one of Rj or Rk is a heteroaryl group such as pyridine,pyridazine, pyrimidine and pyrazine, such as a nicotinate ester.Exemplary esters also include reverse esters having the structure—R_(k)C(O)O—, where the oxygen is bound to the parent molecule.Exemplary reverse esters include succinate, D-argininate, L-argininate,L-lysinate and D-lysinate. Esters also include carboxylic acidanhydrides and acid halides.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedring containing one, two, or three heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Heterocycles can be aromatic(heteroaryls) or non-aromatic. Heterocycles can be substituted with oneor more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Heterocycles also includebicyclic, tricyclic, and tetracyclic groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom aryls, cycloalkyls, and heterocycles. Exemplary heterocyclesinclude acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl,homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl,isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl,pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refer to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy attached toan alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy attached to anaryl group.

The term “ketone” as used herein refers to the structure —C(O)—Rn (suchas acetyl, —C(O)CH₃) or —R_(n-)C(O)—R_(o-). The ketone can be attachedto another group through R_(n) or R_(o). R_(n) or R_(o) can be alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or R_(n) or R_(o)can be joined to form a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.

The term “phenyl” as used herein refers to a 6-membered carbocyclicaromatic ring. The phenyl group can also be fused to a cyclohexane orcyclopentane ring. Phenyl can be substituted with one or moresubstituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone.

The term “thioalkyl” as used herein refers to an alkyl group attached toa sulfur (—S-alkyl-).

“Alkyl,” “alkenyl,” “alkynyl”, “alkoxy”, “amino” and “amide” groups canbe optionally substituted with or interrupted by or branched with atleast one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide, thioketone, ureido and N. The substituentsmay be branched to form a substituted or unsubstituted heterocycle orcycloalkyl.

As used herein, a suitable substitution on an optionally substitutedsubstituent refers to a group that does not nullify the synthetic orpharmaceutical utility of the compounds of the present disclosure or theintermediates useful for preparing them. Examples of suitablesubstitutions include, but are not limited to: C₁₋₈ alkyl, alkenyl oralkynyl; C₁₋₆ aryl, C₇₋₅ heteroaryl; C₃₋₇ cycloalkyl; C₁₋₈ alkoxy; C₆aryloxy; —CN; —OH; oxo; halo, carboxy; amino, such as —NH(C₁₋₈ alkyl),—N(C₁₋₈alkyl)₂, —NH((C₆)aryl), or —N((C₆)aryl)₂; formyl; ketones, suchas —CO(C₁₋₈ alkyl), —CO((C₆aryl) esters, such as —CO₂(C₁₋₈ alkyl) and—CO₂ (C₆aryl). One of skill in art can readily choose a suitablesubstitution based on the stability and pharmacological and syntheticactivity of the compound of the present disclosure.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present disclosurethat are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the presentdisclosure. A discussion is provided in Higuchi et al., “Prodrugs asNovel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present disclosure encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present disclosure can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentdisclosure. The present disclosure encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of thepresent disclosure, even though only one tautomeric structure isdepicted.

EXEMPLARY EMBODIMENTS

In a preferred aspect of Formula I, the invention is directed to acompound according to Formula II:

or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydratethereof,wherein:

-   -   W₁ is selected from N and CR₅;    -   W₂ is selected from N and CR₄;    -   W₃ is selected from N and CR₃, with the proviso that if W₃ is N        then neither R₅ nor R₄ is —OH;    -   each W may be the same or different from each other;    -   R₁ is a carbocycle or heterocycle;    -   V is selected from a 5-membered monocyclic carbocycle or        monocyclic heterocycle, where the heterocycle is connected to        the rest of the molecule via a carbon-carbon bond,    -   with the proviso that V cannot be unsubstituted thiophene,        cyclopentyl, cyclopentenyl, ribofuranosyl, or furan,    -   and with the proviso that if W₁═CR₅ and V is an optionally        substituted

-   -   then at least one of R₃ and R₄ are different from hydrogen, or        if W₃═N, then R₄ is different from hydrogen,    -   and with the proviso that if W₁═CR₅ and V is

-   -    then R₁ is different from

-   -   and with the proviso that if W₁═CR₅ and V is

-   -    then R₁ is not

-   -   and with the proviso that if W₁═N and V is an optionally        substituted

-   -    then at least one of R₃ and R₄ are different from hydrogen, or        if W₃→N, then R₄ is different from hydrogen,    -   and with the proviso that if W₁═N and V is an optionally        substituted

-   -    then R₁-A is different from

-   -   and with the proviso that if W₁═N and V is

-   -    then R₃ and R₄ cannot be

-   -   R₃, R₄, and R₅ are each independently selected from hydrogen,        alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, carbonate, amino, amide, halogen,        carbocycle, heterocycle, sulfone, sulfoxide, sulfide,        sulfonamide, and —CN,    -   with the proviso that if R₅ is —COOMe then V is not a        substituted thiophene,    -   and with the proviso that if R₅ is methyl then R₂ is not

-   -   and with the proviso that if B is present (meaning n is        different from zero) then neither R₄ or R₅ can be hydroxyl;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle;    -   R₄ may be connected to B or V to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₃—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—;    -   with the proviso that R_(x) and R_(y) cannot both be an        unsubstituted phenyl ring,    -   and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then        R₄ is not —OH,    -   and with the proviso that if A is —CH₂CH₂O— or —CH₂C(O)NH— then        V is not a substituted

-   -    or a substituted

-   -   and with the proviso that if A is —CH₂CH₂O— the R₁ is not

-   -   R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or two substituents selected from        R_(x), R_(y), R_(z), R_(v), R₅, and R₁ may be connected in a 5-        or 6-membered ring to form a bicyclic carbocycle or bicyclic        heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;        n is selected from 0 and 1, meaning if n=0 then B is absent; and    -   R_(a), R_(b), R_(c) and R_(d) are each independently selected        from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

In some embodiments, according to Formula II, V is selected from anoptionally substituted 5-membered monocyclic heterocycle, such as, butnot limited to:

In some embodiments according to Formula II, V is optionally substitutedwith hydrogen, alkyl (C₁-C₄)(such as methyl, ethyl, propyl, isopropyl,butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy), amino (suchas —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂, —NEtBu,—NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as —NHC(O)Me,—NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃, ketone(C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄) (such as—S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et, —SO₂Pr),-thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl (such as—COOH), and/or ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and/or thio-oxo.

In some embodiments according to Formula II, V is selected from anoptionally substituted 5-membered monocyclic heterocycle containing oneoxygen and one or two nitrogens, where the heterocycle is connected tothe rest of the molecule via a carbon-carbon bond.

In some embodiments, according to Formula II, V is an optionallysubstituted isoxazole.

In some embodiments, according to Formula II, V is

In some embodiments, according to Formula II, W₁ is CR₅.

In some embodiments, according to Formula II, W₂ is CR₄.

In some embodiments, according to Formula II, X is oxygen.

In some embodiments, according to Formula II, n=0, meaning B is absent.

In some embodiments, according to Formula II, A is selected from C═O and—CR_(x)R_(y)—.

In some embodiments, according to Formula II, R₁ is selected from anoptionally substituted 3-, 4-, 5-, and 6-membered carbocycle orheterocycle (such as cyclopropyl, phenyl, pyridyl, thiophene,cyclobutyl, piperidine, piperazine, cyclopentyl, or cyclohexyl).

In some embodiments, according to Formula II, R₁ is selected from anoptionally substituted 5- and 6-membered carbocycle and heterocycle(such as phenyl, pyridyl, thiophene, or cyclopentyl).

In some embodiments, according to Formula II, R₁ is selected from anoptionally substituted phenyl or pyridyl ring.

In some embodiments, according to Formula II, R₃, R₄, and R₅ are eachindependently selected from hydrogen, alkyl (C₁-C₈), —OH, —NH₂,thioalkyl (C₁-C₈), alkoxy(C₁-C₈) (such as methoxy, ethoxy, —OPr, or-OiPr), ketone(C₁-C₈), ester, carboxylic acid, urea, carbamate,carbonate, amino, amide, halogen (such as F, Cl, Br), carbocycle (suchas cyclopropyl, cyclopentyl, phenyl), alkenyl(C₁-C₈), alkynyl (C₁-C₈),heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN, whichmay be optionally substituted.

In some embodiments, according to Formula II, R₅ is selected fromhydrogen, methyl, —CF₃, Ethyl, propyl, isopropyl, methoxy, ethoxy,propoxy, —NHMe, —NHEthyl, —NHAc, NH₂, and —CN.

In some embodiments, according to Formula II, R₃ is selected fromhydrogen, —CN, —NH₂, amino (such as —NHMe, —NHethyl, —NHcyclopropyl,—NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), amido (such as —NHAc,—NHC(O)Et, —NHC(O)Pr, —NHC(O)phenyl, —C(O)NHMe, —C(O)NH₂, —C(O)NHEt,—C(O)NMe₂), sulfone, Sulfoxide, sulfonamide (such as —SO₂NH₂, —NHSO₂Me),carbocycle (for example, phenyl, cyclopropyl, cyclobutyl, orcyclopentyl), or heterocycle, which may be optionally substituted.

In some embodiments, according to Formula II, R₃ is selected fromhydrogen, —NH₂, amino (such as —NHMe, —NHEt, —NHcyclopropyl, —NHPh,—NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), and —NHheterocycle orheterocycle (such as

which may be optionally substituted with groups independently selectedfrom hydrogen, alkyl (C₁-C₃), —OH, —NH₂, thioalkyl (C₁-C₃), alkoxy(C₁-C₃), ketone (C₁-C₃), ester, carboxylic acid, urea, carbamate,carbonate, amino, amide, and halogen.

In some embodiments, according to Formula II, R₃, R₄, and R₅ may beoptionally substituted with groups independently selected from hydrogen,alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic acid,urea, carbamate, carbonate, amino, amide, and halogen.

In some embodiments, according to Formula II, R₃ and R₄ may be connectedto form an optionally substituted 5-, 6-, or 7-membered carbocycle orheterocycle such as

In some embodiments, according to Formula II, R_(x) and R_(y) areselected from hydrogen, alkyl(C₁-C₃); halogen (such as F and Cl), —CF₃,amino (such as —NHMe, —NHEt, —NHiPr), alkoxy (such as —OMe, OEt, OPr),and —CN.

In some embodiments, according to Formula II, R_(x) and R_(y) areindependently selected from hydrogen, methyl, and —CF₃.

In some embodiments, according to Formula II, R_(x) and R_(v) areindependently selected from hydrogen, methyl, and —CF₃.

In some embodiments, according to Formula II, R_(a), R_(b), R_(c), andR_(d) are independently selected from hydrogen, methyl, methoxy, and—CF₃.

In some embodiments, according to Formula II, B is selected from—(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, —S(O)—, and —SO₂—, where n is 0 or1, meaning if n=0 then B is absent.

In some embodiments, according to Formula II, B is selected from—(CR_(a)R_(b))_(n)—, —O—, —NH—, and —S—, where n is 0 or 1, meaning ifn=0 then B is absent.

In certain embodiments of the invention, the compound of Formula II isselected from:6-(3,5-Dimethylisoxazol-4-yl)-2-phenethylpyridazin-3(2H)-one (Example1);

-   6-(3,5-Dimethylisoxazol-4-yl)-2-(pyridin-2-ylmethyl)pyridazin-3(2H)-one    (Example 2);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(pyrimidin-2-ylmethyl)pyridazin-3(2H)-one    (Example 3);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 4);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one    (Example 5);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyrazin-2(1H)-one (Example 6);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 7);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2(1H)-one (Example    8);-   1-(4-((Dimethylamino)methyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    hydrochloric acid (Example 9);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one    hydrochloric acid (Example 10);-   5-(3,5-Dimethylisoxazol-4-yl)-1-((3,5-dimethylisoxazol-4-yl)methyl)pyridin-2(1H)-one    (Example 11);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methylpyridin-2(1H)-one    (Example 12);-   4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzamide    (Example 13);-   2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one (Example    14);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(quinoxalin-6-ylmethyl)pyridin-2(1H)-one    (Example 18);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one    (Example 19);-   2-Benzyl-4-methyl-6-(5-methylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 20);-   2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one    (example 21);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluorobenzyl)pyridazin-3(2H)-one    (Example 22);-   2-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 23);-   2-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)benzonitrile    (Example 24);-   2-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 25);-   2-(2-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 26);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one    (Example 27);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-methylbenzyl)pyridazin-3(2H)-one    (Example 28);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methylbenzyl)pyridazin-3(2H)-one    (Example 29);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methylbenzyl)pyridazin-3(2H)-one    (Example 30);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one    (Example 31);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluoro-5-methylbenzyl)pyridazin-3(2H)-one    (Example 32);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methoxybenzyl)pyridazin-3(2H)-one    (Example 33);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridazin-3(2H)-one    (Example 34);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methoxybenzyl)pyridazin-3(2H)-one    (Example 35);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one    (Example 36);-   6-(3,5-Dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)pyridazin-3(2H)-one    (Example 37);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one    (Example 38);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one    (Example 39);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethoxy)benzyl)pyridin-2(1H)-one    (Example 40);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methylbenzyl)pyridin-2(1H)-one    (Example 41);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluorobenzyl)pyridin-2(1H)-one    (Example 42);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylpropyl)pyridin-2(1H)-one    (Example 43);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one    (Example 44);-   2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 45);-   5-(3,5-Dimethylisoxazol-4-O-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one    (Example 46);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(quinolin-8-ylmethyl)pyridin-2(1H)-one    (Example 47);-   1-(Cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 48);-   1-(Cyclobutylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 49);-   1-(3-(Difluoromethyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 50);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenoxyethyl)pyridin-2(1H)-one    (Example 51);-   1-((5-Chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 55);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one (Example    56);-   1-Benzyl-5-(5-methylisoxazol-4-yl)pyridin-2(1H)-one (Example 57);

1-Benzyl-5-(isoxazol-4-yl)pyridin-2(1H)-one (Example 58);

-   1-Benzyl-5-(isothiazol-4-yl)pyridin-2(1H)-one (Example 59);-   2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)amino)pyridazin-3(2H)-one    (Example 61);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2(1H)-one    (Example 63);-   1-Benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 64);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methylpyridin-2(1H)-one    (Example 66);-   1-Benzyl-3-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 67);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzoyl)pyridin-2(1H)-one    (Example 68);-   1-(4-Chlorobenzoyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 69);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)pyridin-2(1H)-one    (Example 70);-   N-(1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide    (Example 71);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one    (Example 72);-   3-Amino-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 73);-   1-Benzyl-3-(benzylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 74);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(methylamino)pyridin-2(1H)-one    (Example 75);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one    (Example 76);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(naphthalen-2-ylmethyl)pyridazin-3(2H)-one    (Example 77);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methoxybenzyl)pyridin-2(1H)-one    (Example 78);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one    (Example 79);-   1-Benzyl-5-(thiazol-5-yl)pyridin-2(1H)-one (Example 80);-   1-Benzyl-5-(5-methyl-1H-imidazol-4-yl)pyridin-2(1H)-one (Example    81);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)-4-methylpyridazin-3(2H)-one    (Example 84);-   2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one    (Example 85);-   2-Benzyl-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one    (Example 86);-   6-(3,5-Dimethylisoxazol-4-yl)-4-methyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one    (Example 87);-   2-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 88);-   4-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)-N-methylbenzamide    (Example 89);-   2-(2,6-Difluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 90);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one    (Example 91);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2,4,6-trifluorobenzyl)pyridazin-3(2H)-one    (Example 92);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)pyridazin-3(2H)-one    (Example 93);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H)-one    (Example 94);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-fluorophenyl)ethyl)pyridazin-3(2H)-one    (Example 95);-   2-(2-Chloro-6-fluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 96);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(isoxazol-4-ylmethyl)pyridazin-3(2H)-one    (Example 97);-   5-(5-Amino-3-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one    trifluoroacetic acid (Example 98);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 101);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(quinolin-8-ylmethyl)pyridazin-3(2H)-one    (Example 102);-   1-(1-(2-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 103);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 104);-   1-(1-(4-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 105);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenylpropan-2-yl)pyridin-2(1H)-one    (Example 106);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(thiophen-3-ylmethyl)pyridazin-3(2H)-one    (Example 107);-   (R)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one    (Example 108);-   (S)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one    (Example 109);-   (S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 110);-   (R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 111);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one    (Example 112);-   1-(1-(3-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 113);-   1-Benzyl-6-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 114);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-6-methylpyridin-2(1H)-one    (Example 115);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methylbenzyl)pyridin-2(1H)-one    (Example 121);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methylbenzyl)pyridin-2(1H)-one    (Example 122);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 123);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 124);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 125);-   1-(3-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 126);-   1-(2-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 127);-   1-(4-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 128);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one    (Example 129);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one    (Example 130);-   1-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 131);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one    (Example 132);-   (S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 133);-   (R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 134);-   2-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile    (Example 135);-   1-(2,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 136);-   4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile    (Example 137);-   1-(2,4-Difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 138);-   1-(4-Chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 139);-   1-(2-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 140);-   1-(4-Chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 141);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3,4,5-trifluorobenzyl)pyridin-2(1H)-one    (Example 142);-   2-((1H-Benzo[d]imidazol-5-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 143);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3,4,5-trifluorobenzyl)pyridazin-3(2H)-one    (Example 144);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(methylsulfonyl)benzyl)pyridin-2(1H)-one    (Example 145);-   1-((1H-Benzo[d]imidazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 146);-   1-(3-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 147);-   1-((1H-Indazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 148);-   1-((1H-Indol-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 149);-   1-((4-Chlorophenyl)sulfonyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 150);-   5-(3-Amino-5-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one (Example    151);-   3-Amino-1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 152);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-methylpiperazin-1-yl)pyridin-2(1H)-one    Hydrochloride (Example 153);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methoxypyridin-2(1H)-one    (Example 154);-   1-(3,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 155);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((4-fluorophenyl)amino)pyridin-2(1H)-one    (Example 156);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3-fluorophenyl)amino)pyridin-2(1H)-one    (Example 157);-   1-Benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 158);-   1-(4-Chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 159);-   1-Benzyl-5-(3-methylisothiazol-4-yl)pyridin-2(1H)-one (Example 160);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(piperazin-1-yl)pyridin-2(1H)-one    Hydrochloride (Example 161);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methoxybenzyl)pyridin-2(1H)-one    (Example 162);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(pyrimidin-2-ylmethyl)pyridin-2(1H)-one    (Example 163);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one (Example    167);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2H-phthalazin-1-one (Example    170);-   6-Benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one    (Example 173);-   7-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one    (Example 174);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one    (Example 175);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one    (Example 176);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one    (Example 180);-   3-chloro-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one    (Example 181);-   5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-(phenylamino)pyridin-2(1H)-one    (Example 182);-   3-(azetidin-1-yl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 183);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((1-methyl-1H-pyrazol-3-yl)amino)pyridin-2(1H)-one    (Example 184);-   3-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide    (Example 185);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(ethylamino)pyridin-2(1H)-one    (Example 186);-   1-benzyl-5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 187);-   1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one    (Example 188);-   3-amino-1-benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 189);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-morpholinopyridin-2(1H)-one    (Example 190);-   1-benzyl-3-(benzyloxy)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 191);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(isopropylamino)pyridin-2(1H)-one    (Example 192);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylamino)pyridin-2(1H)-one    (Example 193);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-3-ylamino)pyridin-2(1H)-one    (Example 194);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-4-ylamino)pyridin-2(1H)-one    (Example 195);-   1-benzyl-5-(3,5-dimethylisothiazol-4-yl)pyridin-2(1H)-one (Example    196);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile    (Example 198);-   methyl    4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylate    (Example 199);-   N-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methanesulfonamide    (Example 200);-   2-benzyl-6-(((3,5-dimethylisoxazol-4-yl)methyl)amino)pyridazin-3(2H)-one    (Example 201);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxamide    (Example 202);-   3-amino-1-(4-chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 203);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(1H-imidazol-1-yl)pyridin-2(1H)-one    (Example 204);-   3-amino-1-(4-chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 205);-   3-amino-1-(4-chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 206);-   3-amino-1-(2-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 207);-   1-benzyl-3-(cyclopentylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 208);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-hydroxypyridin-2(1H)-one    (Example 209);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methoxypyridin-2(1H)-one    (Example 210);-   3-amino-1-(3,4-difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 211);-   3-amino-1-(3-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 212);-   3-amino-1-(3,4-dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 213);-   1-benzyl-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 214);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-2-ylmethyl)pyridin-2(1H)-one    (Example 215);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile    (Example 216);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3,5-dimethylisoxazol-4-yl)amino)pyridin-2(1H)-one    (Example 217);-   5-(3,5-dimethylisoxazol-4-yl)-1-(4-vinylbenzyl)pyridin-2(1H)-one    (Example 218);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one    (Example 219);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one    (Example 220);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridazin-3-ylamino)pyridin-2(1H)-one    (Example 221);-   3-amino-1-((5-chlorothiophen-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 222);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-fluoropyridin-3-yl)amino)pyridin-2(1H)-one    (Example 223);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-methylpyridin-2(1H)-one    (Example 224);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylic    acid (Example 225);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one    (Example 226);-   3-amino-1-(2-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 227);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 228);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic    acid (Example 229);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide    (Example 230);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(5-methoxypyridin-3-yl)amino)pyridin-2(1H)-one    (Example 231);-   5-((1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)picolinonitrile    (Example 232);-   4-amino-2-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 233);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methoxypyridin-3-yl)amino)pyridin-2(1H)-one    (Example 234);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrazin-2-ylamino)pyridin-2(1H)-one    (Example 235);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrimidin-5-ylamino)pyridin-2(1H)-one    (Example 236);-   3-amino-1-(4-(azetidin-1-yl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 237);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-morpholinobenzyl)pyridin-2(1H)-one    (Example 238);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrrolidin-3-ylamino)pyridin-2(1H)-one    (Example 239);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)pyridin-2(1H)-one    (Example 240);-   3-amino-1-(4-bromobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 241);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-isopropylbenzyl)pyridin-2(1H)-one    (Example 242);-   1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-((2,2,2-trifluoroethyl)amino)pyridin-2(1H)-one    (Example 243);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one    (Example 244);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methylpyridin-3-yl)amino)pyridin-2(1H)-one    (Example 245);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methylpyridin-3-yl)amino)pyridin-2(1H)-one    (Example 246);    −1-((1H-indol-4-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 247);-   2-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one    (Example 248);-   4-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methoxy-N,5-dimethylisoxazole-3-carboxamide    (Example 249);-   4-amino-2-benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 250);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((2,5-dimethylthiophen-3-yl)methyl)pyridin-2(1H)-one    (Example 251);-   3-amino-1-((5-chloropyridin-3-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 252);-   3-amino-1-(3-chloropyridin-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 253);-   3-amino-1-((3-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 254);-   3-amino-1-((5-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 255);-   3-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 256);-   3-amino-1-(benzo[d][1,3]dioxol-4-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 257);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-3-yl)methyl)pyridin-2(1H)-one    (Example 258);-   methyl    4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylate    (Example 259);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylic    acid (Example 260);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-fluorobenzonitrile    (Example 261);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-fluorobenzonitrile    (Example 262);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 263);-   5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)thiophene-2-carbonitrile    (Example 264);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-N,3-dimethylisoxazole-5-carboxamide    (Example 265);-   3-(aminomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 266);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-iodobenzyl)pyridin-2(1H)-one    (Example 267);-   1-benzyl-5-(5-oxopyrrolidin-3-yl)pyridin-2(1H)-one (Example 268);-   4-(1-(3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile    (Example 269);-   1-((1H-indol-3-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 270);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methyl-1H-indol-4-yl)methyl)pyridin-2(1H)-one    (Example 271);-   5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile    (Example 272);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile    (Example 276); and-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(quinolin-5-ylmethyl)pyridin-2(1H)-one    (Example 274).

In certain embodiments of the disclosure, the compound of formula I is1-(4-chlorobenzyl)-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one(Example 197).

In a second aspect of Formula I, the invention is directed to a compoundaccording to Formula III:

-   -   or a stereoisomer, tautomer, pharmaceutical acceptable salt, or        hydrate thereof, wherein:    -   W₂ is selected from N and CR₄,    -   with the proviso that if W₂ is N and R₂ is

-   -    then R₅ is not hydrogen;    -   W₃ is selected from N and CR₃,    -   with the proviso that if W₃ is N then neither R₅ or R₄ can be        —OH;    -   each W may be the same or different from each other;    -   R₁ is a carbocycle or heterocycle,    -   with the proviso R₁-A is not

-   -   and with the proviso that if R₁-A is

-   -    then at least one of Q₁, Q₂, Q₃, or Q₄ is different from        hydrogen,    -   and with the proviso that if R₁-A is

-   -    then at least one of R₃ and R₄ is not hydrogen,    -   and with the proviso that if R₁ is

-   -    then R₂ is not

-   -   and with the proviso that if R₁ is

-   -    then R₂ is not

-   -   R₂ is selected from a 6-membered monocyclic carbocycle or        monocyclic heterocycle, with the proviso that R₂ is not

-   -    or an optionally substituted

-   -   and with the proviso that if R₂ is

-   -    then at least one of R₃ and R₄ is not hydrogen,    -   and with the proviso that if R₃ is —CN, then R₂ is not

-   -   and with the proviso that if R₂ is

-   -    then R₁ is not

-   -   and with the proviso that if R₂ is

-   -    then R₅ is not —COOMe    -   and with the proviso that if R₄ is —NH₂ then R₂ is not

-   -   R₃, R₄, and R₅ are each independently selected from hydrogen,        alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, carbonate, amino, amide, halogen,        carbocycle, heterocycle, sulfone, sulfoxide, sulfide,        sulfonamide, and —CN,    -   with the proviso that R₄ is not —OH and R₅ is not —COOH or        -ester;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle;    -   R₄ may be connected to B or R₂ to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—;    -   with the proviso that R_(x) and R_(y) cannot both be an        unsubstituted phenyl ring,    -   and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then        R₄ is not —OH,    -   and with the proviso that if A is —CH₂CH₂O— the R₁ is not

-   -   R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or two substituents selected from        R_(x), R_(y), R_(z), R_(v), R₅, and R₁ may be connected in a 5-        or 6-membered ring to form a bicyclic carbocycle or bicyclic        heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent;    -   and R_(a), R_(b), R_(c), and R_(d) are each independently        selected from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

In some embodiments, according to Formula III, R₂ is selected from anoptionally substituted 6-membered monocyclic carbocycle (such as phenyl)or heterocycle (such as pyridyl, pyrimidine, pyrazine, and triazine),where the heterocycle is connected to the rest of the molecule via acarbon-carbon bond.

In some embodiments, according to Formula III, R₂ is selected from

wherein:W_(a) is selected from N and CQ₁;W_(b) is selected from N and CQ₂;W_(e) is selected from N and CQ₃;W_(d) is selected from N and CQ₄;W_(e) is selected from N and CQ₅;Each W may be the same or different from each other;Q₁, Q₂, Q₄, Q₅ are each independently selected from hydrogen, —OH, —NH₂,halogen, —CF₃, —CN, —Ac, alkyl(C₁-C₃), alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃), —N(Alkyl)₂ (C₁-C₃),which may be optionally substituted with groups independently selectedfrom F, Cl, Br, —OH, —NH₂, —OMe, —OEt, —NHMe, —SMe, —S(O)Me, -Me, and-Et;Q₃ is selected from —OH, —NH₂, F, Cl, alkyl(C₁-C₃), alkoxy(C₁-C₃),—S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃),and —N(Alkyl)₂ (C₁-C₃), which may be optionally substituted with groupsindependently selected from F, Cl, —OH, —NH₂, —OMe, —OEt, -Me, and -Et.

In some embodiments, according to Formula III, R₂ is selected from

In some embodiments, according to Formula III, R₁ is selected from a 3-,4-, 5-, or 6-membered carbocycle or heterocycle.

In some embodiments, according to Formula III, R₁ is selected from anoptionally substituted phenyl.

In some embodiments, according to Formula III, R₁ is optionallysubstituted with hydrogen, —OH, —NH₂, halogen, —CF₃, —CN, —Ac,Alkyl(C₁-C₃), Alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃),—SAlkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂ (C₁-C₃), which may beoptionally substituted.

In some embodiments, according to Formula III, R₃ is selected fromhydrogen, —CN, —NH₂, amino (such as —NHMe, —NHethyl, —NHcyclopropyl,—NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), amido (such as —NHAc,—NHC(O)Et, —NHC(O)Pr, —NHC(O)phenyl, —C(O)NHMe, —C(O)NH₂, —C(O)NHEt,—C(O)NMe₂), sulfone, Sulfoxide, sulfonamide (such as —SO₂NH₂, —NHSO₂Me),carbocycle (phenyl, cyclopropyl, cyclobutyl, or cyclopentyl), andheterocycle, which may be optionally substituted.

In some embodiments, according to Formula III, R₃ is selected fromhydrogen, —NH₂, amino (such as —NHMe, —NHEt, —NHcyclopropyl, —NHPh,—NHBn, —NMe₂, —NHpyridyl, or —NHcyclopentyl), and —NHheterocycle orheterocycle (such as,

which may be optionally substituted with groups independently selectedfrom hydrogen, alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester,carboxylic acid, urea, carbamate, carbonate, amino, amide, halogen, oxo,and thio-oxo.

In some embodiments, according to Formula III, R₃, R₄, and R₅ may beoptionally substituted with groups independently selected from hydrogen,alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic acid,urea, carbamate, carbonate, amino, amide, and halogen.

In some embodiments, according to Formula III, R₃ and R₄ may beconnected to form an optionally substituted 5-, 6-, or 7-memberedcarbocycle or heterocycle such as

In some embodiments, according to Formula III, R₅ is hydrogen.

In some embodiments, according to Formula III, R₄ is hydrogen.

In some embodiments, according to Formula III, X is oxygen.

In some embodiments, according to Formula III, n=0, meaning B is absent.

In some embodiments, according to Formula III, B is selected from—(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, where n is 0 or 1, meaning if n=0then B is absent.

In some embodiments, according to Formula III, A is selected from C═Oand —CR_(x)R_(y)—

In certain embodiments of the invention, the compound of Formula III isselected from: 1-Benzyl-5-(3,4,5-trimethoxyphenyl)pyridin-2(1H)-one(Example 52);

-   2-((2-Oxo-5-(3,4,5-trimethoxyphenyl)pyridin-1(2H)-yl)methyl)benzonitrile    (Example 53);-   1-Benzyl-2′-hydroxy-[3,4′-bipyridin]-6(1H)-one (Example 62);-   1-Benzyl-5-((3,4-dimethoxyphenyl)amino)pyridin-2(1H)-one (Example    65);-   2-Benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one (Example 166);-   2-Benzyl-4-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one (Example    168);-   2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)isoquinolin-1(2H)-one (Example    169); and-   2-Benzyl-4-((3,4,5-trimethoxyphenyl)amino)isoquinolin-1(2H)-one    (Example 172).

In a third aspect of Formula I, the invention concerns a compoundaccording to Formula IV:

-   -   or a stereoisomer, tautomer, pharmaceutically acceptable salt,        or hydrate thereof,    -   wherein:    -   W₂ is selected from N and CR₄,    -   with the proviso that if W₂ is N and R₂ is

-   -    then R₅ is not hydrogen;    -   W₃ is selected from N and CR₃,    -   with the proviso that if W₃ is N then neither R₅ or R₄ can be        —OH;    -   each W may be the same or different from each other;    -   R₁ is a carbocycle or heterocycle,    -   with the proviso that R₁ is different from an amino group with        nitrogen attached to A (such as

-   -    a substituted napthyl, or cyclohexyl,    -   and with the proviso that R₁-A is not

-   -   and with the proviso that if R₁-A is

-   -    then R₂ is not an optionally substituted

-   -    where T is halogen,    -   and with the proviso that if R₁-A is

-   -    then R₂ is not

-   -   and with the proviso that if R₁A is

-   -    then R₂ is not substituted with —OH or —NH₂;    -   R₂ is selected from a 6-membered monocyclic carbocycle or        monocyclic heterocycle,    -   with the proviso that R₂ is not unsubstituted thiophene, furane,        cyclopentyl, cyclohexyl, or

-   -    where T can be any atom,    -   and with the proviso that R₂ is not

-   -    where T is Cl, Br, —OMe, or Me,    -   and with the proviso that R₂ is not

-   -    where T and Y are independently selected from Cl, F, -Me, —CN,        and —OH,    -   and with the proviso that R₂ is not

-   -   and with the proviso that if R₂ is

-   -    then R₁-A is not

-   -    where T and Y are independently selected from hydrogen, F, Cl,        Br, —CF₃, and -Me, and R₁ is not unsubstituted pyridyl,        substituted furane, or unsubstituted naphthyl,    -   and with the proviso that if R₂ is

-   -    where T is an —OH, Alkoxy, —OAcyl, —NH₂, amino, amide,        carbamate, or urea, substituent, then at least one of R₃ and R₄        is different from hydrogen,    -   and with the proviso that if R₂ is an unsubstituted pyridyl,        then at least one of R₃ and R₄ is different from hydrogen, or        R₁-A is different from

-   -    or R₃ and R₄ are not connected to form an unsubstituted benzene        ring,    -   and with the proviso that if R₂ is

-   -    then R₃ is not methyl, at least one of R₃ and R₄ cannot be        connected to

-   -    or R₁-A cannot be

-   -   R₃ and R₄ are each independently selected from hydrogen, alkyl,        —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic acid,        urea, carbamate, carbonate, amino, amide, halogen, carbocycle,        heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN,    -   with the proviso that R₄ is not —OH;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle,    -   with the proviso that R₃ and R₄ are not connected to form

-   -   -   R₄ may be connected to B or R₂ to form a carbocycle or            heterocycle;

    -   X is selected from O and S;

    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R^(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)C_(z)R_(v)CR_(Q)R_(R)—;

    -   with the proviso that if A is C═O, then R₂ is not an optionally        substituted

-   -    where T is halogen,    -   and with the proviso that R_(x) and R_(y) cannot both be an        unsubstituted phenyl ring,    -   and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then        R₄ is not —OH,    -   and with the proviso that if A is —CH₂CH₂O— the R₁ is not

-   -   R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or    -   two substituents selected from R_(x), R_(y), R_(z), R_(v), R₅,        and R₁ may be connected in a 5- or 6-membered ring to form a        bicyclic carbocycle or bicyclic heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent;    -   R_(a), R_(b), R_(c), and R_(d) are each independently selected        from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

In some embodiments, according to Formula IV, R₂ is selected from anoptionally substituted 6-membered monocyclic carbocycle (such as phenyl)or heterocycle (such as pyridyl, pyrimidine, pyrazine, and triazine),where the heterocycle is connected to the rest of the molecule via acarbon-carbon bond.

In some embodiments, according to Formula IV, R₂ is selected from

wherein:W_(a) is selected from N and CQ₁;W_(b) is selected from N and CQ₂;W_(c) is selected from N and CQ₃;W_(d) is selected from N and CQ₄;W_(e) is selected from N and CQ₅;Each of W_(a), W_(b), W_(c), W_(d), and W_(e) may be the same ordifferent from each other;Q₁, Q₂, Q₄, Q₅ are each independently selected from hydrogen, —OH, —NH₂,halogen, —CF₃, —CN, —Ac, alkyl(C₁-C₃), alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂(C₁-C₃), which may be optionally substituted with groups independentlyselected from F, Cl, Br, —OH, —NH₂, —OMe, —OEt, —NHMe, —SMe, —S(O)Me,-Me, and -Et;Q₃ is selected from —OH, —NH₂, F, Cl, alkyl(C₁-C₃), alkoxy(C₁-C₃),—S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃),and —N(Alkyl)₂ (C₁-C₃), which may be optionally substituted with groupsindependently selected from F, Cl, —OH, —NH₂, —OMe, —OEt, -Me, and -Et.

In some embodiments, according to Formula IV, R₂ is selected from

In some embodiments, according to Formula IV, R₁ is selected from a 3-,4-, 5-, or 6-membered carbocycle or heterocycle.

In some embodiments, according to Formula IV, R₁ is selected from anoptionally substituted phenyl.

In some embodiments, according to Formula IV, R₁ is optionallysubstituted with hydrogen, —OH, —NH₂, halogen, —CF₃, —CN, —Ac,Alkyl(C₁-C₃), Alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃),—SAlkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂ (C₁-C₃), which may beoptionally substituted.

In some embodiments, according to Formula IV, R₃ is selected fromhydrogen, —CN, —NH₂, amino (such as —NHMe, —NHethyl, —NHcyclopropyl,—NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), amido (such as —NHAc,—NHC(O)Et, —NHC(O)Pr, —NHC(O)phenyl, —C(O)NHMe, —C(O)NH₂, —C(O)NHEt,—C(O)NMe₂), sulfone, Sulfoxide, sulfonamide (such as —SO₂NH₂, —NHSO₂Me),carbocycle (phenyl, cyclopropyl, cyclobutyl, cyclopentyl), andheterocycle, which may be optionally substituted.

In some embodiments, according to Formula IV, R₃ is selected fromhydrogen, —NH₂, amino (such as —NHMe, —NHEt, —NHcyclopropyl, —NHPh,—NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), and —NHheterocycle orheterocycle (such as,

which may be optionally substituted with groups independently selectedfrom hydrogen, alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester,carboxylic acid, urea, carbamate, carbonate, amino, amide, and halogen.

In some embodiments, according to Formula IV, R₃, R₄, and R₅ may beoptionally substituted with groups independently selected from hydrogen,alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic acid,urea, carbamate, carbonate, amino, amide, and halogen.

In some embodiments, according to Formula IV, R₃ and R₄ may be connectedto form an optionally substituted 5-, 6-, or 7-membered carbocycle orheterocycle such as

In some embodiments, according to Formula IV, R₄ is hydrogen.

In some embodiments, according to Formula IV, X is oxygen.

In some embodiments, according to Formula IV, n=0, meaning B is absent.

In some embodiments, according to Formula IV, B is selected from—(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, where n is 0 or 1, meaning if n=0then B is absent.

In some embodiments, according to Formula IV, A is selected from C═O and—CR_(x)R_(y)—

In certain embodiments of the invention, the compound of Formula IV isselected from:3-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile(Example 15);

-   4-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile    (Example 16);-   N-(3-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)phenyl)acetamide    (Example 17);-   2-Benzyl-6-((3,4,5-trimethoxyphenyl)amino)pyridazin-3(2H)-one    (Example 54);-   2-Benzyl-6-((3,4-dimethoxyphenyl)amino)pyridazin-3(2H)-one (Example    60);-   N-(4-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)phenyl)acetamide    (Example 82);-   2-Benzyl-6-(4-hydroxy-3-methoxyphenyl)pyridazin-3(2H)-one (Example    83);-   2-Benzyl-6-((5,6-dimethoxypyridin-2-yl)amino)pyridazin-3(2H)-one    (Example 99);-   2-Benzyl-6-(3,4-dimethoxyphenoxy)pyridazin-3(2H)-one (Example 100);-   2-(4-(Methylsulfonyl)benzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 116);-   2-(4-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 117);-   2-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile    (Example 118);-   2-(3-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 119);-   2-(4-(tert-Butyl)benzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 120);-   2-Benzyl-4-(2-hydroxy-3,4-dimethoxyphenyl)phthalazin-1(2H)-one    (Example 164);-   2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)-2H-phthalazin-1-one (Example    165);-   2-Benzyl-4-(3,4,5-trimethoxyphenylamino)-2H-phthalazin-1-one    (Example 171);-   2-Benzyl-4-(2,3,4-trimethoxyphenyl)phthalazin-1(2H)-one (Example    177);-   6-(4-hydroxyphenyl)-2-(1-phenylethyl)pyridazin-3(2H)-one (Example    178); and-   2-benzyl-6-(4-methyl-3-oxopiperazin-1-yl)pyridazin-3(2H)-one    (Example 179).

Another aspect of the invention provides a method for inhibition of BETprotein function by binding to bromodomains, and their use in thetreatment and prevention of diseases and conditions in a mammal (e.g., ahuman) comprising administering a therapeutically effective amount of acompound of Formulae I-IV.

In one embodiment, because of potent effects of BET inhibitors in vitroon IL-6 and IL-17 transcription, BET inhibitor compounds of FormulaeI-IV may be used as therapeutics for inflammatory disorders in whichIL-6 and/or IL-17 have been implicated in disease. The followingautoimmune diseases are amenable to therapeutic use of BET inhibition byadministration of a compound of Formulae I-IV because of a prominentrole of IL-6 and/or IL-17: Acute Disseminated Encephalomyelitis [69],Agammaglobulinemia [70], Allergic Disease [71], Ankylosing spondylitis[72], Anti-GBM/Anti-TBM nephritis [73], Anti-phospholipid syndrome [74],Autoimmune aplastic anemia [75], Autoimmune hepatitis [76], Autoimmuneinner ear disease [77], Autoimmune myocarditis [78], Autoimmunepancreatitis [79], Autoimmune retinopathy [80], Autoimmunethrombocytopenic purpura [81], Behcet's Disease [82], Bullous pemphigoid[83], Castleman's Disease [84], Celiac Disease [85], Churg-Strausssyndrome [86], Crohn's Disease [87], Cogan's syndrome [88], Dry eyesyndrome [89], Essential mixed cryoglobulinemia [90], Dermatomyositis[91], Devic's Disease [92], Encephalitis [93], Eosinophlic esophagitis[94], Eosinophilic fasciitis [94], Erythema nodosum [95], Giant cellarteritis [96], Glomerulonephritis [97], Goodpasture's syndrome [73],Granulomatosis with Polyangiitis (Wegener's) [98], Graves' Disease [99],Guillain-Barre syndrome [100], Hashimoto's thyroiditis [101], Hemolyticanemia [102], Henoch-Schonlein purpura [103], IgA nephropathy [104],Inclusion body myositis [105], Type I diabetes [8], Interstitialcystitis [106], Kawasaki's Disease [107], Leukocytoclastic vasculitis[108], Lichen planus [109], Lupus (SLE) [110], Microscopic polyangitis[111], Multiple sclerosis [112], Myasthenia gravis [113], myositis [91],Optic neuritis [114], Pemphigus [115], POEMS syndrome [116],Polyarteritis nodosa [117], Primary biliary cirrhosis [118], Psoriasis[119], Psoriatic arthritis [120], Pyoderma gangrenosum [121], Relapsingpolychondritis [122], Rheumatoid arthritis [123], Sarcoidosis [124],Scleroderma [125], Sjogren's syndrome [126], Takayasu's arteritis [127],Transverse myelitis [128], Ulcerative colitis [129], Uveitis [130], andVitiligo [131].

Acute and chronic (non-autoimmune) inflammatory diseases characterizedby increased expression of pro-inflammatory cytokines, including IL-6,MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition.These include, but are not limited to, sinusitis [132], pneumonitis[133], osteomyelitis [134], gastritis [135], enteritis [136], gingivitis[137], appendicitis [138], irritable bowel syndrome [139], tissue graftrejection [140], chronic obstructive pulmonary disease (COPD) [141],septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc) [12],osteoarthritis [142], acute gout [143], acute lung injury [141], acuterenal failure [144], burns [145], Herxheimer reaction and SIRSassociated with viral infections [8].

In one embodiment, BET inhibitor compounds of Formulae I-IV may be usedfor treating rheumatoid arthritis (RA) and multiple sclerosis (MS).Strong proprietary data exist for the utility of BET inhibitors inpreclinical models of RA and MS [17]. Both RA and MS are characterizedby a dysregulation of the IL-6 and IL-17 inflammatory pathways [10] andthus would be especially sensitive to BET inhibition. In anotherembodiment, BET inhibitor compounds of Formulae I-IV may be used fortreating sepsis and associated afflictions. BET inhibition has beenshown to inhibit development of sepsis, in part, by inhibiting IL-6expression, in preclinical models in both published [12] and proprietarydata.

In one embodiment, BET inhibitor compounds of Formulae I-IV may be usedto treat cancer. Cancers that have an overexpression, translocation,amplification, or rearrangement c-myc or other myc family oncoproteins(MYCN, L-myc) are particularly sensitive to BET inhibition [27, 28].These cancers include, but are not limited to, B-acute lymphocyticleukemia, Burkitt's lymphoma, Diffuse large cell lymphoma, Multiplemyeloma, Primary plasma cell leukemia, Atypical carcinoid lung cancer,Bladder cancer, Breast cancer, Cervix cancer, Colon cancer, Gastriccancer, Glioblastoma, Hepatocellular carcinoma, Large cellneuroendocrine carcinoma, Medulloblastoma, Melanoma, nodular, Melanoma,superficial spreading, Neuroblastoma, esophageal squamous cellcarcinoma, Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clearcell carcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lungcarcinoma [25].

In one embodiment, BET inhibitor compounds of Formulae I-IV may be usedto treat cancers that result from an aberrant regulation(overexpression, translocation, etc) of BET proteins. These include, butare not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation tonutlin 1 gene) [22], B-cell lymphoma (Brd2 overexpression) [23],non-small cell lung cancer (BrdT overexpression) [147, 148], esophagealcancer and head and neck squamous cell carcinoma (BrdT overexpression)[147], and colon cancer (Brd4) [149].

In one embodiment, because BET inhibitors decrease Brd-dependentrecruitment of pTEFb to genes involved in cell proliferation, BETinhibitor compounds of Formulae I-IV may be used to treat cancers thatrely on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes.These include, but are not limited to, chronic lymphocytic leukemia andmultiple myeloma [150], follicular lymphoma, diffuse large B celllymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin'slymphoma, follicular lymphomas and activated, anaplastic large celllymphoma [151], neuroblastoma and primary neuroectodermal tumor [152],rhabdomyosarcoma [153], prostate cancer [154], and breast cancer [45].

In one embodiment, BET inhibitor compounds of Formulae I-IV may be usedto treat cancers in which BET-responsive genes, such as CDK6, Bcl2,TYRO3, MYB, and hTERT are up-regulated [26, 27]. These cancers include,but are not limited to, pancreatic cancer, breast cancer, colon cancer,glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia,malignant glioma, bladder cancer, medulloblastoma, thyroid cancer,melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostatecancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantlecell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer,and renal carcinoma [32, 155-162].

Published and proprietary data have shown direct effects of BETinhibition on cell proliferation in various cancers. In one embodiment,BET inhibitor compounds of Formulae I-IV may be used to treat cancersfor which exist published and, for some, proprietary, in vivo and/or invitro data showing a direct effect of BET inhibition on cellproliferation. These cancers include NMC(NUT-midline carcinoma), acutemyeloid leukemia (AML), acute B lymphoblastic leukemia (B-ALL),Burkitt's Lymphoma, B-cell Lymphoma, Melanoma, mixed lineage leukemia,multiple myeloma, pro-myelocytic leukemia (PML), and non-Hodgkin'slymphoma [24, 26-30, 33]. Examples provided within this application havealso shown a direct effect of BET inhibition on cell proliferation invitro for the following cancers: Neuroblastoma, Medulloblastoma, lungcarcinoma (NSCLC, SCLC), and colon carcinoma.

In one embodiment, because of potential synergy or additive effectsbetween BET inhibitors and other cancer therapy, BET inhibitor compoundsof Formulae I-IV may be combined with other therapies, chemotherapeuticagents, or anti-proliferative agents to treat human cancer and otherproliferative disorders. The list of therapeutic agents which can becombined with BET inhibitors in cancer treatment includes, but is notlimited to, ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281(Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib(Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide(Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX),Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide,Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090),Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa₂a (RoferonA), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin,Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin),PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone),Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib(Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine(Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130(Degrasyn).

In one embodiment, because of their ability to up-regulate ApoA-1transcription and protein expression [11, 35], BET inhibitor compoundsof Formulae I-IV may be used to treat cardiovascular diseases that aregenerally associated with including dyslipidemia, atherosclerosis,hypercholesterolemia, and metabolic syndrome [8, 19]. In anotherembodiment, BET inhibitor compounds of Formulae I-IV may be used totreat non-cardiovascular disease characterized by deficits in ApoA-1,including Alzheimer's disease [37].

In one embodiment, BET inhibitor compounds of Formulae I-IV may be usedin patients with insulin resistance and type II diabetes [8, 19, 38,39]. The anti-inflammatory effects of BET inhibition would haveadditional value in decreasing inflammation associated with diabetes andmetabolic disease [163].

In one embodiment, because of their ability to down-regulate viralpromoters, BET inhibitor compounds of Formulae I-IV may be used astherapeutics for cancers that are associated with viruses includingEpstein-Barr Virus (EBV), hepatitis virus (HBV, HCV), Kaposi's sarcomaassociated virus (KSHV), human papilloma virus (HPV), Merkel cellpolyomavirus, and human cytomegalovirus (CMV) [40-42, 164]. In anotherembodiment, because of their ability to reactivate HIV-1 in models oflatent T cell infection and latent monocyte infection, BET inhibitorscould be used in combination with anti-retroviral therapeutics fortreating HIV [43-46].

In one embodiment, because of the role of epigenetic processes andbromodomain-containing proteins in neurological disorders, BET inhibitorcompounds of Formulae I-IV may be used to treat diseases including, butnot limited to, Alzheimer's disease, Parkinson's disease, Huntingtondisease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, andepilepsy [9, 165].

In one embodiment, because of the effect of BRDT depletion or inhibitionon spermatid development, BET inhibitor compounds of Formulae I-IV maybe used as reversible, male contraceptive agents [50, 51].

Pharmaceutical Compositions

Pharmaceutical compositions of the present disclosure comprise at leastone compound of Formulae I-IV, or tautomer, stereoisomer,pharmaceutically acceptable salt or hydrate thereof formulated togetherwith one or more pharmaceutically acceptable carriers. Theseformulations include those suitable for oral, rectal, topical, buccaland parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous) administration. The most suitable form of administration inany given case will depend on the degree and severity of the conditionbeing treated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the presentdisclosure as powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such formulations may be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation at least one compound of the present disclosure as theactive compound and a carrier or excipient (which may constitute one ormore accessory ingredients). The carrier must be acceptable in the senseof being compatible with the other ingredients of the formulation andmust not be deleterious to the recipient. The carrier may be a solid ora liquid, or both, and may be formulated with at least one compounddescribed herein as the active compound in a unit-dose formulation, forexample, a tablet, which may contain from about 0.05% to about 95% byweight of the at least one active compound. Other pharmacologicallyactive substances may also be present including other compounds. Theformulations of the present disclosure may be prepared by any of thewell-known techniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of thepresent disclosure as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe present disclosure with a liquid or finely divided solid carrier, orboth, and then, if necessary, shaping the product. For example, a tabletmay be prepared by compressing or molding a powder or granules of atleast one compound of the present disclosure, which may be optionallycombined with one or more accessory ingredients. Compressed tablets maybe prepared by compressing, in a suitable machine, at least one compoundof the present disclosure in a free-flowing form, such as a powder orgranules, which may be optionally mixed with a binder, lubricant, inertdiluent and/or surface active/dispersing agent(s). Molded tablets may bemade by molding, in a suitable machine, where the powdered form of atleast one compound of the present disclosure is moistened with an inertliquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the present disclosure in aflavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the at least one compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Formulations of the present disclosure suitable for parenteraladministration comprise sterile aqueous preparations of at least onecompound of Formulae I-IV or tautomers, stereoisomers, pharmaceuticallyacceptable salts, and hydrates thereof, which are approximately isotonicwith the blood of the intended recipient. These preparations areadministered intravenously, although administration may also be effectedby means of subcutaneous, intramuscular, or intradermal injection. Suchpreparations may conveniently be prepared by admixing at least onecompound described herein with water and rendering the resultingsolution sterile and isotonic with the blood. Injectable compositionsaccording to the present disclosure may contain from about 0.1 to about5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formulae I-IV ortautomers, stereoisomers, pharmaceutically acceptable salts, andhydrates thereof) is generally present at a concentration of from about0.1% to about 15% w/w of the composition, for example, from about 0.5 toabout 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and the following Table for Equivalent Surface AreaDosage Factors).

Equivalent Surface Area Dosage Factors:

To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8 kg) (60kg) Mouse 1 1/2 1/4 1/6  1/12 Rat 2 1 1/2 1/4 1/7 Monkey 4 2 1 3/5 1/3Dog 6 4 3/5 1 1/2 Human 12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

In one embodiment, a compound of Formulae I-IV or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, isadministered in combination with another therapeutic agent. The othertherapeutic agent can provide additive or synergistic value relative tothe administration of a compound of the present disclosure alone. Thetherapeutic agent can be, for example, a statin; a PPAR agonist, e.g., athiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; abile-acid reuptake inhibitor; a cholesterol absorption inhibitor; acholesterol synthesis inhibitor; a cholesteryl ester transfer protein(CETP), an ion-exchange resin; an antioxidant; an inhibitor of AcylCoAcholesterol acyltransferase (ACAT inhibitor); a tyrophostine; asulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; anapolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomaltriglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug;an HDL enhancer; a regulator of the apolipoprotein A-IV and/orapolipoprotein genes; or any cardiovascular drug.

In another embodiment, a compound of Formulae I-IV or a tautomer,stereoisomer, pharmaceutically acceptable salt or hydrate thereof, isadministered in combination with one or more anti-inflammatory agents.Anti-inflammatory agents can include immunosuppressants, TNF inhibitors,corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs),disease-modifying anti-rheumatic drugs (DMARDS), and the like. Exemplaryanti-inflammatory agents include, for example, prednisone;methylprenisolone (Medrol®), triamcinolone, methotrexate (Rheumatrex®,Trexall®), hydroxychloroquine (Plaquenil®), sulfasalzine (Azulfidine®),leflunomide (Arava®), etanercept (Enbrel®), infliximab (Remicade®),adalimumab (Humira®), rituximab (Rituxan®), abatacept (Orencia®),interleukin-1, anakinra (Kineret™), ibuprofen, ketoprofen, fenoprofen,naproxen, aspirin, acetominophen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine, or sulfasalazine.

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EXAMPLES General Procedure A: Preparation of2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one Example 14

Step 1:

To a solution of 1 (2.0 g, 15.3 mmol) in acetonitrile (30 mL) was addedbenzyl bromide (2.18 mL, 18.4 mmol), tetrabutylammoniumbromide (0.25 g,0.77 mmol) and potassium carbonate (5.3 g, 38.3 mmol). The reaction washeated at 90° C. for 16 h. The reaction mixture was cooled to roomtemperature, concentrated and purified by chromatography (silica gel,0-20% ethyl acetate/hexanes) to give 2 (2.2 g, 60%) as a white solid: ¹HNMR (300 MHz, CDCl₃) δ 7.47-7.40 (m, 2H), 7.39-7.28 (m, 3H), 7.16 (d,J=9.6 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H).

Step 2:

To a solution of 2 (100 mg, 0.45 mmol) in 1,4-dioxane (3 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(103 mg, 0.46 mmol), sodium carbonate (2.0 M in H₂O, 0.27 mL, 0.54 mmol)and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.023 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with methylene chloride (20 mL) and washed withbrine (15 mL). The organic layer was dried over sodium sulfate, filteredand concentrated. Purification by chromatography (silica gel, 0-40%ethyl acetate/hexanes) afforded Example 14 (65 mg, 51%) as an off-whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.48-7.40 (m, 2H), 7.40-7.27 (m, 4H),7.02 (d, J=9.6 Hz, 1H), 5.36 (s, 2H), 2.46 (s, 3H), 2.32 (s, 3H); ESIm/z 282 [M+H]⁺.

General Procedure B: Preparation of2-Benzyl-64(5,6-dimethoxypyridin-2-yl)-amino)pyridazin-3(2H)-one Example99

A mixture of 2-benzyl-6-chloropyridazin-3(2H)-one (2) (220 mg, 1.0mmol), 5,6-dimethoxypyridin-2-amine (3) (231 mg, 1.5 mmol), BINAP (125mg, 0.2 mmol) and sodium tert-butoxide (106 mg, 1.1 mmol) in 1,4-dioxane(15 mL) was purged with nitrogen for 5 minutes.Tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.1 mmol) was added andthe reaction mixture was heated to 100° C. for 16 h. The reaction wasdiluted with EtOAc (100 mL), washed with brine (50 mL) and the ethylacetate solution was separated, dried (Na₂SO₄) and concentrated. Theresidue was purified by chromatography (silica gel, 10%-60%EtOAc/CH₂Cl₂) to yield Example 99 (153 mg, 45%) as a yellow solid: ¹HNMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 7.52 (d, J=9.9 Hz, 1H), 7.36-7.25(m, 7H), 6.93 (d, J=9.9 Hz, 1H), 5.15 (s, 2H), 3.84 (s, 3H), 3.72 (s,3H); ESI MS m/z 339 [M+H]⁺.

General Procedure C: Preparation of2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one Example 28

Step 1:

To a solution of 4 (5.5 g, 36.9 mmol) in ethanol (170 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(9.88 g, 44.3 mmol), sodium carbonate (2.0 M in H₂O, 36.9 mL, 73.8 mmol)and tetrakis(triphenylphosphine)palladium(0) (1.0 g, 1.85 mmol). Thereaction mixture was purged with nitrogen and then heated at 90° C. for5 h. The mixture was concentrated to half of the volume, then dilutedwith ethyl acetate (200 mL) and washed with brine (2×30 mL). The ethylacetate layer was dried over sodium sulfate, filtered and concentrated.Purification by chromatography (silica gel, 0-40% ethyl acetate/hexanes)afforded 5 (4.26 g, 55%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.04 (d, J=9.0 Hz, 1H), 7.99 (d, J=9.0 Hz, 1H), 2.59 (s, 3H), 2.39 (s,3H).

Step 2:

To a solution of 5 (4.26 g, 20.4 mmol) in water (25 mL) was added aceticacid (25 mL). The reaction mixture was refluxed at 105° C. for 16 h. Thereaction was cooled to room temperature and neutralized with 6 N aq.sodium hydroxide solution (100 mL). The solids were collected, washedwith water and dried in a vacuum oven to afford 6 (2.8 g, 75%) as ayellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (s, 1H), 7.63 (d, J=9.6Hz, 1H), 6.99 (d, I=9.6 Hz, 1H), 2.49 (s, 3H), 2.29 (s, 3H).

Step 3:

To a solution of 6 (40 mg, 0.21 mmol) in acetonitrile (2 mL) was added2-methylbenzyl bromide (0.034 ml, 0.25 mmol) and potassium carbonate (58mg, 0.42 mmol). The reaction was heated at 80° C. for 16 h. The reactionmixture was cooled to room temperature, concentrated and purified bychromatography (silica gel, 0-50% ethyl acetate/hexanes) to affordExample 28 (39 mg, 62%) as a brown-red solid: ¹H NMR (300 MHz, DMSO-d₆)δ 7.69 (d, J=9.0 Hz, 1H), 7.25-7.06 (m, 5H), 5.31 (s, 2H), 2.40 (s, 3H),2.31 (s, 3H), 2.15 (s, 3H); ESI m/z 296 [M+H]⁺.

General Procedure D: Preparation of5-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one(Example 27)

Step 1:

To a solution of 7 (150 mg, 0.86 mmol) in acetonitrile (3 mL) was added1-(bromomethyl)-2-fluorobenzene (0.13 ml, 1.03 mmol) and potassiumcarbonate (237 mg, 1.72 mmol). The reaction was heated at 80° C. for 16h. The reaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-20% ethyl acetate/hexanes) togive 8 (180 mg, 74%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.10(d, J=2.8 Hz, 1H), 7.58 (dd, J=9.9, 2.8 Hz, 1H), 7.42-7.30 (m, 1H),7.28-7.08 (m, 3H), 6.42 (d, J=9.7 Hz, 1H), 5.12 (s, 2H).

Step 2:

To a solution of 8 (180 mg, 0.64 mmol) in 1,4-dioxane (4 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(170 mg, 0.76 mmol), 2 M aq. sodium carbonate (0.48 mL, 0.95 mmol) andtetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with methylene chloride (30 mL) and washed withbrine (2×10 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. Purification by chromatography (silica gel,0-45% ethyl acetate/hexanes) afforded Example 27 (48 mg, 25%) as a whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=2.4 Hz, 1H), 7.54 (dd,J=6.6 Hz, 2.7 Hz, 1H), 7.41-7.30 (m, 1H), 7.29-7.14 (m, 3H), 6.51 (d,J=9.3 Hz, 1H), 5.18 (s, 2H), 2.20 (s, 3H), 1.99 (s, 3H); ESI m/z 299[M+H]⁺.

General Procedure E: Preparation of5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(3-fluorophenyl)ethyl)pyridin-2(1H)-oneExample 104

Step 1:

A solution of 7 (522 mg, 3.0 mmol), 1-(3-fluorophenyl)ethanol (631 mg,14.5 mmol) and PPh₃ (1.18 g, 4.5 mmol) in THF (10 mL) was cooled to 0°C. DIAD (0.87 mL, 4.5 mmol) was added dropwise and the reaction wasstirred at room temperature for 3 h. The mixture was concentrated andpurified by chromatography (silica gel, 50% ethyl acetate/hexanes) togive 9 (257 mg, 29%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.39-7.30 (m, 2H), 7.17 (d, J=2.7 Hz, 1H), 7.11-7.06 (m, 2H), 7.02 (dd,J=9.9, 1.2 Hz, 1H), 6.54 (dd, J=9.9, 1.2 Hz, 1H), 6.36 (q, J=7.2 Hz,1H), 1.71 (d, J=7.2 Hz, 3H).

Step 2:

To a solution of 9 (148 mg, 0.50 mmol) in 1,4-dioxane (6 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(167 mg, 0.75 mmol), 2 M aq. Na₂CO₃ (0.50 mL, 1.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol). Thereaction mixture was purged with nitrogen and then heated at 80° C. for6 h. The mixture was diluted with EtOAc (50 mL) and washed with brine(20 mL). The ethyl acetate layer was dried over sodium sulfate, filteredand concentrated. Purification by chromatography (silica gel, 20-80%ethyl acetate/hexanes) followed by recrystallization from ethylacetate/hexanes afforded Example 104 (84 mg, 54%) as an off-white solid:¹H NMR (300 MHz, DMSO-d₆) δ 7.70 (d, J=2.4 Hz, 1H), 7.47 (dd, J=9.3, 2.4Hz, 1H), 7.40 (dd, J=7.8, 6.0 Hz, 1H), 7.26-7.12 (m, 3H), 6.52 (d, J=9.3Hz, 1H), 6.20 (q, J=7.2 Hz, 1H), 2.29 (s, 3H), 2.12 (s, 3H), 1.75 (d,J=7.2 Hz, 3H); ESI-MS m/z 313 [M+H]⁺.

General Procedure F: Preparation of1-Benzyl-5-(thiazol-5-yl)pyridin-2(1H)-one Example 80

Step 1:

A mixture of 5-bromopyridin-2(1H)-one (7, 3.0 g, 17.2 mmol), benzylbromide (4.4 g, 25.8 mmol), potassium carbonate (4.8 g, 34.5 mmol) andacetonitrile (150 mL) was heated at 70° C. for 3 h under nitrogen. Themixture was allowed to cool to room temperature and the solvent wasremoved under reduced pressure. The residue was purified bychromatography (silica gel, eluting with 0-75% EtOAc/hexanes), toprovide 10 (3.84 g, 84%) as a white solid: ¹H NMR (500 MHz, CDCl₃) δ7.38-7.29 (m, 7H), 6.53 (d, J=9.4 Hz, 1H), 5.09 (s, 2H).

Step 2:

A mixture of bis(pinacolato)diboron (2.23, 9.94 mmol), 10 (500 mg, 2.19mmol), Pd(dppf)Cl₂ (390 mg, 0.47 mmol), KOAc (2.79 g, 28.4 mmol) and DMF(15 mL) was heated at 80° C. under nitrogen for 16 h. The reactionmixture was then cooled and poured over ice. The mixture was extractedwith EtOAc (3×100 mL) and the combined extracts were dried over sodiumsulfate and filtered. The solvent was removed under reduced pressure andthe residue was purified by chromatography (silica gel, 0-50% EtOAc inhexanes) to provide 11 (2.3 g, 78%) as an off-white solid: ¹H NMR (500MHz, CDCl₃) δ 7.78 (d, J=1.9 Hz, 1H), 7.59 (dd, J=2.0, 9.1 Hz, 1H),7.33-7.28 (m, 5H), 6.56 (d, =9.1 Hz, 1H), 5.15 (s, 2H), 1.28 (s, 12H).

Step 3:

A mixture of 11 (200 mg, 0.64 mmol), 5-bromothiazole (157 mg, 0.96mmol), potassium carbonate (177 mg, 1.28 mmol),tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.04 mmol), dioxane (6mL) and water (1 mL) was heated at 90° C. for 16 h. The reaction mixturewas cooled and concentrated under reduced pressure. The residue waspurified by chromatography (silica gel, 0-100% EtOAc in hexanes) toprovide Example 80 (38 mg, 22%) as a white solid: ¹H NMR (500 MHz,CDCl₃) δ 8.69 (s, 1H), 7.82 (s, 1H), 7.53 (dd, J=2.1, 9.1 Hz, 1H), 7.50(d, J=2.4 Hz, 1H), 7.38-7.32 (m, 5H), 6.71 (d, J=9.5 Hz, 1H), 5.12 (s,2H); ESI MS m/z 269 [M+H]⁺.

General Procedure G: Preparation of1-(3-(Difluoromethyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-oneExample 50

Step 1:

To a solution of 12 (5.6 g, 29.9 mmol) in 1,4-dioxane (120 mL) and water(24 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(8.0 g, 35.9 mmol), sodium carbonate (6.34 g, 59.8 mmol) andtetrakis(triphenylphosphine)palladium(0) (863 mg, 0.75 mmol). Thereaction mixture was purged with nitrogen and was heated at 100° C. for16 h. The mixture was diluted with methylene chloride (200 mL) andwashed with brine (2×50 mL). The combined extracts were dried oversodium sulfate, filtered and concentrated. Purification bychromatography (silica gel, 0-15% ethyl acetate/hexanes) afforded 13(5.4 g, 89%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.20 (dd,J=2.5 Hz, 0.6 Hz, 1H), 7.76 (dd, J=8.6 Hz, 2.5 Hz, 1H), 6.93 (dd, J=8.5Hz, 0.7 Hz, 1H), 3.89 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H).

Step 2:

To a solution of 13 (4.40 g, 21.5 mmol) in ethanol (130 mL) was addedhydrobromic acid (48%, 44 mL) and the reaction mixture was refluxed at90° C. for 4 h. The reaction mixture was cooled to room temperature andconcentrated. The residue was dissolved in methanol and neutralized topH 8 by adding potassium carbonate. After stirring the mixture for 30min, the suspension was filtered and the filtrate was concentrated.Purification by chromatography (silica gel, 0-10% methanol/ethylacetate) afforded 14 (3.5 g, 85%) as a yellow solid: ¹H NMR (300 MHz,DMSO-d₆) δ 11.85 (br s, 1H), 7.50-7.40 (m, 2H), 6.41 (dd, J=9.2 Hz, 0.8Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H).

Step 3:

To a solution of 14 (100 mg, 0.53 mmol) in acetonitrile (2 mL) andN,N-dimethyl formamide (1 mL) was added1-(bromomethyl)-3-(difluoromethyl)benzene (174 mg, 0.79 mmol) andpotassium carbonate (219 mg, 1.59 mmol). The reaction was heated at 80°C. for 16 h. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-65% ethylacetate/hexanes) to give Example 50 (150 mg, 86%) as a yellow solid: ¹HNMR (300 MHz, DMSO-d₆) δ 7.99 (d, J=2.1 Hz, 1H), 7.57 (s, 1H), 7.55-7.47(m, 4H), 7.04 (q, J=56 Hz, 1H), 6.52 (d, J=9.3 Hz, 1H), 5.19 (s, 2H),2.36 (s, 3H), 2.19 (s, 3H); ESI m/z 331 [M+H]⁺.

General Procedure H: Preparation of5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzoyl)pyridin-2(1H)-oneExample 68

A mixture of 5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one (15, 60 mg,0.32 mmol), NEt₃ (64 mg, 2 equiv.) and 4-fluorobenzoyl chloride (75 mg,1.5 equiv.) in 1,4-dioxane (5 mL) was stirred at room temperature for 16h. The reaction mixture was concentrated and purified by chromatography(silica gel, 0-40% EtOAc in hexanes) to afford the Example 68 (75 mg,76%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.37 (d, J=2.4 Hz,1H), 8.25-8.30 (m, 2H), 7.76 (dd, J=2.4, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz,2H), 7.19-7.24 (m, 2H), 2.46 (s, 3H), 2.31 (s, 3H). ESI MS m/z 313[M+H]⁺.

General Procedure I: Preparation of1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)pyridin-2(1H)-oneExample 70

A mixture of1-benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one (16,130 mg, 0.41 mmol), 4-fluorophenylboronic acid (115 mg, 2 equiv.),Pd(OAc)₂ (28 mg, 0.1 equiv), S-Phos (34 mg, 0.2 equiv.) and K₃PO₄ (174mg, 2 equiv.) in wet toluene (5 mL mixed with 0.5 mL H₂O) was stirred at100° C. for 16 h. The reaction mixture was allowed to cool to roomtemperature and filtered through a layer of Celite. The filtrate wasconcentrated and then purified by chromatography (silica gel, 0-20%EtOAc in CH₂Cl₂) to afford Example 70 (58 mg, 38%) as a pale red solid:¹H NMR (300 MHz, CDCl₃) δ 7.67-7.72 (m, 2H), 7.36-7.40 (m, 5H), 7.34 (d,J=2.4 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.08-7.14 (m, 2H), 5.25 (s, 2H),2.34 (s, 3H), 2.20 (s, 3H). ESI MS m/z 375 [M+H]⁺.

General Procedure J: Preparation of1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-oneExample 72

A mixture of1-benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one (16, 90mg, 0.29 mmol), aniline (54 mg, 2 equiv.), Pd₂(dba)₃ (27 mg, 0.1 equiv),rac-BINAP (36 mg, 0.2 equiv.) and Cs₂CO₃ (189 mg, 2 equiv.) in toluene(4 mL) was stirred at 110° C. for 16 h. The reaction mixture was allowedto cool to room temperature and was filtered through a layer of Celite.The filtrate was concentrated and purified by chromatography (silicagel, 0-50% EtOAc in hexanes) to afford Example 72 (61 mg, 57%) as ayellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (s, 1H); 7.43-7.34 (m,5H); 7.25-7.32 (m, 5H); 6.98 (d, J=2.1 Hz, 1H); 6.90-6.96 (m, 1H); 5.22(s, 2H); 2.36 (s, 3H); 2.19 (s, 3H); ESI MS m/z 372 [M+H]⁺.

General Procedure K Chiral Separation of Example 110 and Example 111

The enantiomeric mixture of received as Example 101 (80 mg) wereseparated by preparative HPLC (column: Chiralcel OD, 5 cm×50 cm, 20micron); mobile phase: 10% EtOH in hexanes; flow rate: 80 mL/min;detection: 254 nm) to afford Example 110 (the first eluting enantiomer,white solid, 30 mg, 38%) and Example 111 (the second eluting enantiomer,white solid, 21 mg, 26%). Example 110: ¹H NMR (300 MHz, DMSO-d₆) δ 7.65(d, J=2.1 Hz, 1H), 7.48-7.41 (m, 3H), 7.23-7.17 (m, 2H), 6.51 (d, J=9.3Hz, 1H), 6.20 (q, J=7.2 Hz, 1H), 2.27 (s, 3H), 2.11 (s, 3H), 1.73 (d,J=7.2 Hz, 3H); ESI MS m/z 313 [M+H]⁺; Chiralcel OD (10% EtOH in heptane,0.8 mL/min): t_(R)=11.07 min. Example 111: ¹H NMR (300 MHz, DMSO-d₆) δ7.65 (d, J=2.1 Hz, 1H), 7.48-7.41 (m, 3H), 7.23-7.17 (m, 2H), 6.51 (d,J=9.3 Hz, 1H), 6.20 (q, J=7.2 Hz, 1H), 2.27 (s, 3H), 2.11 (s, 3H), 1.73(d, J=7.2 Hz, 3H); ESI MS m/z 313 [M+H]⁺; Chiralcel OD (10% EtOH inheptane, 0.8 mL/min): t_(R)=18.19 min.

General Procedure L: Preparation of14(1H-benzo[d]imidazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-oneExample 146

To a solution of 17 (100 mg, 0.53 mmol), (1H-benzo[d]imidazol-5-yl)methanol (234 mg, 1.58 mmol) and triphenylphosphine (689 mg, 2.63 mmol)in THF (30 mL) at 60° C. was added diisopropylazodicarboxylate (531 mg,2.63 mmol) dropwise. The reaction was stirred at room temperature for 1h. The reaction mixture was concentrated and purified by chromatography(silica gel, CH₂Cl₂ to 1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH).A portion of this material was further purified by reverse phase HPLCeluting with 10-90% CH₃CN in H₂O to give Example 146 (46 mg, 27%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.96 (d,J=2.5 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.47 (dd, J=2.6,9.3 Hz, 1H), 7.27 (dd, J=1.6, 8.3 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 5.23(s, 2H), 2.34 (s, 3H), 2.17 (s, 3H). ESI MS m/z 321 [M+H]⁺.

General Procedure M: Preparation of1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(piperazin-1-yl)pyridin-2(1H)-oneHydrochloride Example 161

Step 1:

A mixture of 3,5-dibromopyridin-2(1H)-one (18, 3.0 g, 11.9 mmol), benzylbromide (1.7 mL, 14.2 mmol), potassium carbonate (4.9 g, 35.6 mmol) andacetonitrile (90 mL) was heated at reflux for 2 h under nitrogen. Themixture was allowed to cool to room temperature and the solvent wasremoved under reduced pressure. The residue was purified bychromatography (silica gel, eluting with 0-55% EtOAc/hexanes) to provide19 (3.42 g, 84%) as a light yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.77(d, J=2.5 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.38-7.32 (m, 5H), 5.14 (s,2H).

Step 2:

A mixture of 1-benzyl-3,5-dibromopyridin-2(1H)-one (19, 98 mg, 0.29mmol), tert-butyl piperazine-1-carboxylate (107 mg, 2 equiv.), Pd₂(dba)₃(27 mg, 0.1 equiv), rac-BINAP (36 mg, 0.2 equiv.) and Cs₂CO₃ (189 mg, 2equiv.) in toluene (4 mL) was stirred at 110° C. for 16 h. The reactionmixture was allowed to cool to room temperature and was filtered througha layer of Celite. The filtrate was concentrated and purified bychromatography (silica gel, 0-50% EtOAc in hexanes) to afford 20 (69 mg,54%) as a green viscous oil: ¹H NMR (500 MHz, CDCl₃) δ 7.35-7.29 (m,5H), 7.10 (d, J=2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 5.10 (s, 2H),3.61-3.59 (m, 4H), 3.11-3.09 (m, 4H), 1.48 (s, 9H); ESI MS m/z 448[M+H]⁺.

Step 3:

To a solution of 20 (68 mg, 0.15 mmol) in 1,4-dioxane (3 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(51 mg, 0.23 mmol), sodium carbonate (2.0 M in H₂O, 0.5 mL, 1.0 mmol)and tetrakis(triphenylphosphine)-palladium(0) (9 mg, 0.0076 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 15 h.The mixture was diluted with methylene chloride (20 mL) and washed withbrine (15 mL). The methylene chloride layer was dried over sodiumsulfate, filtered and the filtrate was concentrated. Purification bychromatography (silica gel, 0-50% ethyl acetate/hexanes) afforded ayellow viscous oil (41 mg, 58%). This material was dissolved in methanol(1 mL) and 2 M HCl in diethyl ether (1 mL) was added. After stirring atroom temperature for 18 h, the residue was dried in vacuo to affordExample 161 (32 mg, 90%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ8.96 (br s, 2H), 7.65 (d, J=2.2 Hz, 1H), 7.35-7.28 (m, 5H), 6.80 (d,J=2.2 Hz, 1H), 5.15 (s, 2H), 3.37-3.28 (m, 4H), 3.24-3.14 (m, 4H), 2.37(s, 3H), 2.20 (s, 3H); ESI m/z 365 [M+H]⁺.

General Procedure N: Preparation of3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-oneExample 180

Step 1:

To a solution of 21 (500 mg, 2.65 mmol) in acetonitrile (7 mL) and DMF(3.5 mL) was added 1-(bromomethyl)-4-fluorobenzene (0.39 ml, 3.18 mmol)and potassium carbonate (731 mg, 5.30 mmol). The reaction was heated at80° C. for 5 h. The reaction mixture was cooled to room temperature,diluted with ethyl acetate (200 mL) and washed with brine (2×100 mL).The ethyl acetate layer was dried over sodium sulfate, filtered andconcentrated. Purification by chromatography (silica gel, 0-40% ethylacetate/hexanes) provided 22 (360 mg, 46%) as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 7.41-7.36 (m, 2H), 7.30 (d, J=2.4 Hz, 1H), 7.20-7.14 (m,2H), 6.46 (d, J=2.4 Hz, 1H), 5.54 (br s, 2H), 5.04 (s, 2H).

Step 2:

To a solution of 22 (360 mg, 1.21 mmol) in 1,4-dioxane (12 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(323 mg, 1.45 mmol), 2 M aq. sodium carbonate (1.21 mL, 2.42 mmol) andtetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol). Thereaction mixture was purged with nitrogen and heated at 80° C. for 16 h.The mixture was diluted with ethyl acetate (100 mL) and washed withbrine (50 mL). The organic layer was dried over sodium sulfate, filteredand concentrated. Purification by chromatography (silica gel, 10-40%ethyl acetate/hexanes) followed by trituration with ethylacetate/hexanes afforded Example 180 (234 mg, 62%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.45-7.40 (m, 2H), 7.21-7.15 (m, 2H),7.13 (d, J=2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 5.29 (s, 2H), 5.11 (s,2H), 2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 314 [M+H]⁺.

General Procedure O: Preparation of3-Amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methyl-1H-indol-4-yl)methyl)pyridin-2(1H)-oneExample 271

Step 1:

To a solution of 23 (1.52 g, 10.0 mmol) in ethanol (10 mL) was addedpropionaldehyde (696 mg, 12.0 mmol) at room temperature. The mixture washeated at 80° C. for 1 h and cooled at room temperature. Thenconcentrated hydrochloric acid (2.5 mL) was added and heated at 80° C.overnight. The mixture was concentrated under vacuum. The residue wasdissolved in MeOH and basified with sodium carbonate (20% in water). Themixture was concentrated and purified by chromatography (silica gel,0-50% ethyl acetate/hexanes) to give a mixture of 24 and 25 (650 mg,32%) as an orange oil.

Step 2:

To a solution of LiAlH₄ (1 M in THF, 12.8 mL, 12.8 mmol) intetrahydrofuran (50 mL) was added a mixture of 24 and 25 (650 mg, 3.20mmol) in tetrahydrofuran (10 mL) at 0° C. under nitrogen. The reactionmixture was heated at 65° C. for 30 min and then cooled to 0° C. Water(1 mL), 2N aq. NaOH (2 mL), and silica gel (5 g) were then addedsequentially. The mixture was concentrated and purified bychromatography (silica gel, 0-100% ethyl acetate/hexanes) to give:Compound 26 (94 mg, 18%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ7.96 (s, 1H), 7.31 (dd, J=8.1, 0.8 Hz, 1H), 7.14 (t, J=7.2 Hz, 1H), 7.08(d, J=7.2 Hz, 1H), 6.99 (q, J=1.1 Hz, 1H), 5.06 (d, J=5.8 Hz, 2H), 2.53(d, J=1.0 Hz, 3H), 1.56 (t, J=5.9 Hz, 1H). Compound 27 (147 mg, 29%) asan orange solid: ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.35 (d, J=0.5 Hz, 1H), 7.12 (dd, J=8.1, 1.3 Hz, 1H), 6.97 (q,J=1.0 Hz, 1H), 4.78 (d, J=5.4 Hz, 2H), 2.33 (d, J=1.1 Hz, 3H), 1.61 (t,J=5.7 Hz, 1H).

Step 3:

To a solution of 28 (10.0 g, 49.3 mmol) in 1,4-dioxane (400 mL) andwater (40 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(13.2 g, 59.1 mmol), potassium carbonate (13.6 g, 98.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (1.71 g, 1.48 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C.overnight. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-50% ethylacetate/hexanes) to give 29 (9.26 g, 86%) as a yellow solid: ¹H NMR (500MHz, CDCl₃) δ 7.45 (d, J=2.0 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 4.02 (s,3H), 3.87 (s, 2H), 2.37 (s, 3H), 2.23 (s, 3H).

Step 4:

A mixture of 29 (4.00 g, 18.3 mmol), ethanol (15 mL), and 48% HBr (20mL) was heated at 85° C. for 1 h under nitrogen. The reaction mixturewas concentrated under vacuum to give crude 30 (6.40 g) that was used inthe next step without further purification.

Step 5:

To a solution of 30 (6.40 g, 18.3 mmol) and triethylamine (12.7 mL, 91.5mmol) in methylene chloride (100 mL) was added acetic anhydride (3.73 g,36.6 mmol). The mixture was stirred at room temperature for 17 h,methanol (20 mL) was added, and the material was concentrated andpurified by chromatography (silica gel, 0-20% ethyl acetate/methanol).The product was further purified by dissolving in methanol (300 mL) andprecipitation by the addition of water (1000 mL) to give 31 (3.90 g,86%) as a green solid: ¹H NMR (500 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.35(s, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 2.35 (s, 3H),2.17 (s, 3H), 2.12 (s, 3H); ESI m/z 248 [M+H]⁺.

Step 6:

To a solution of 5 (94 mg, 0.58 mmol), 31 (120 mg, 0.49 mmol), andtriphenylphosphine (321 mg, 1.23 mmol) in tetrahydrofuran (10 mL) at 65°C. under nitrogen was added diisopropyl azodicarboxylate (247 mg, 1.23mmol). The mixture was cooled to room temperature, concentrated, andpurified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) togive crude 32 (230 mg, contained Ph₃PO).

Step 7:

A solution of crude 32 (230 mg, 0.490 mmol) and LiOH (118 mg, 4.90 mmol)in 1,4-dioxane (10 mL) and water (10 mL) was heated at 100° C. for 17 hunder nitrogen. The reaction mixture was cooled to room temperature,concentrated and purified by chromatography (silica gel, 0-100%hexanes/ethyl acetate). It was further purified by reverse phase HPLC ona Polaris column eluting with 10-90% CH₃CN in H₂O to give Example 271(32 mg, 19% over 2 steps) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 10.85 (s, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.12-7.95 (m, 1H),6.97 (t, J=7.4 Hz, 1H), 6.69 (d, J=2.5 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H),6.44 (d, J=7.8 Hz, 1H), 5.58 (s, 2H), 5.28 (s, 2H), 2.37 (d, J=0.5 Hz,3H), 2.22 (s, 3H), 2.05 (s, 3H); ESI m/z 349 [M+H]⁺.

General Procedure P: Preparation of3-Amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-isopropylbenzyl)pyridin-2(1H)-oneExample 242

Step 1:

To a solution ofN-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide31 (200 mg, 50% pure, 0.405 mmol) in acetonitrile (10 mL) was added 33(136 mg, 0.810 mmol) and potassium carbonate (168 mg, 1.22 mmol). Thereaction was heated at 60° C. for 17 h. The reaction mixture was cooledto room temperature, concentrated, and purified by chromatography(silica gel, 0-100% ethyl acetate/hexanes) to afford 34 (120 mg, 78%) asan off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.43 (s, 1H), 8.34 (d,J=2.3 Hz, 1H), 7.23 (s, 4H), 6.85 (d, J=2.3 Hz, 1H), 5.17 (s, 2H), 2.90(octet, J=6.9 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 1.23(d, J=6.9 Hz, 6H); ESI m/z 380 [M+H]⁺.

Step 2:

A solution of 34 (100 mg, 0.264 mmol) and LiOH (40 mg, 1.58 mmol) in1,4-dioxane (4 mL) and water (2 mL) was heated at 100° C. for 17 h undernitrogen. The reaction mixture was cooled to room temperature, treatedwith acetic acid (0.5 mL), and concentrated. The residue was purified byreverse phase HPLC on a Polaris column eluting with 10-90% CH₃CN in H₂Oto give Example 242 (75 mg, 84%) as a yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 7.27 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 7.08 (d,J=2.2 Hz, 1H), 6.43 (d, J=2.2 Hz, 1H), 5.25 (s, 2H), 5.08 (s, 2H), 2.84(octet, J=6.9 Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H), 1.17 (d, J=6.9 Hz,6H); ESI m/z 338 [M+H]⁺.

Example 100 Preparation of2-Benzyl-6-(3,4-dimethoxyphenoxy)pyridazin-3(2H)-one

Step 1:

To a solution of 4 (600 mg, 4.0 mmol) in DMF (10 mL) was added3,4-dimethoxyphenol (21, 925 mg, 6.0 mmol) and Cs₂CO₃ (3.91 g, 12.0mmol). The reaction mixture was heated at 110° C. for 10 h. The mixturewas diluted with ethyl acetate (150 mL) and washed with brine (2×30 mL).The ethyl acetate layer was dried over sodium sulfate, filtered andconcentrated. Purification by chromatography (silica gel, 0-40% ethylacetate/hexanes) afforded 22 (480 mg, 45%) as a yellow solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.92 (d, J=9.3 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H),7.00 (d, J=8.7 Hz, 1H), 6.92 (d, J=2.7 Hz, 1H), 6.76 (dd, J=8.7, 2.7 Hz,1H), 3.77 (s, 3H), 3.73 (s, 3H).

Step 2:

A suspension of 22 (480 mg, 1.80 mmol) in water (4 mL) and formic acid(4 mL) was heated to reflux for 10 h. The reaction mixture was cooled toroom temperature and adjusted to pH 8 with 6 N aq. NaOH. Solids werecollected, washed with water and dried to afford 23 (250 mg, 56%) as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 7.36 (d,J=9.9 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 6.85 (d,J=3.0 Hz, 1H), 6.68 (dd, J=8.7, 2.7 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H).

Step 3:

To a solution of 23 (75 mg, 0.30 mmol) in acetonitrile (5 mL) was addedbenzyl bromide (0.043 ml, 0.36 mmol) and potassium carbonate (83 mg,0.60 mmol). The reaction was heated at 80° C. for 16 h. The reactionmixture was cooled to room temperature and the solid filtered was rinsedwith CH₂Cl₂ (10 mL). The filtrate was concentrated and purified bychromatography (silica gel, 10-60% ethyl acetate/hexanes) to giveExample 100 (52 mg, 51%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.38 (d, J=9.6 Hz, 1H), 7.32-7.20 (m, 5H), 7.09 (d, J=9.6 Hz, 1H), 6.93(d, J=8.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 6.67 (dd, J=8.7, 2.7 Hz, 1H),5.03 (s, 2H), 3.74 (s, 3H), 3.66 (s, 3H); ESI MS m/z 339 [M+H]⁺.

Example 151 Preparation of5-(3-Amino-5-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one

Step 1:

A mixture of 4-bromo-5-methylisoxazol-3-amine (18, 0.35 g, 2 mmol),(6-methoxypyridin-3-yl)boronic acid (0.46 g, 1.5 equiv.),PdCl₂dppf.CH₂Cl₂ (146 mg, 0.1 equiv) and Cs₂CO₃ (1.3 g, 2 equiv.) inaqueous DME (6 mL mixed with 0.5 mL H₂O) was stirred at 100° C. for 5 h.The reaction mixture was allowed to cool to room temperature andfiltered through a layer of Celite. The filtrate was concentrated andpurified by chromatography (silica gel, 0-50% EtOAc in hexanes) toafford 19 (93 mg, 23%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆)δ 8.15 (dd, J=0.6, 2.4 Hz, 1H), 7.69 (dd, J=2.4, 8.7 Hz, 1H), 6.90 (dd,J=0.6, 8.4 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 3H), 2.25 (s, 3H). ESI MS m/z206 [M+H]⁺.

Step 2:

A mixture of 4-(6-methoxypyridin-3-yl)-5-methylisoxazol-3-amine (19,0.33 g, 1.6 mmol) and HBr (4 mL, 48% aqueous solution) in EtOH (6 mL)was stirred at 85° C. for 8 h. The reaction mixture was allowed to coolto room temperature and Na₂CO₃ was added until pH reached 7-8. Themixture was filtered through a layer of Celite and the filtrate wasconcentrated. The material was purified by chromatography (silica gel,0-10% CH₃OH in CH₂Cl₂) to afford 20 (0.22 g, 71%) as an off-white solid:¹H NMR (300 MHz, DMSO-d₆) δ 11.8 (s, 1H), 7.40 (dd, J=2.7, 9.3 Hz, 1H),7.32 (d, J=2.1 Hz, 1H), 6.39 (d, J=9.6 Hz, 1H), 5.39 (s, 2H), 2.21 (s,3H). ESI MS m/z 192 [M+H]⁺.

Step 3:

A mixture of 5-(3-amino-5-methylisoxazol-4-yl)pyridin-2(1H)-one (20, 53mg, 0.28 mmol), K₂CO₃ (77 mg, 2 equiv.) and benzyl bromide (52 mg, 1.1equiv.) in CH₃CN (4 mL) was stirred at 85° C. in sealed tube for 12 h.The reaction mixture was allowed to cool to room temperature and wasfiltered through a layer of Celite. The filtrate was concentrated andpurified by trituration with ethyl acetate to afford Example 151 (71 mg,90%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (d, J=2.1Hz, 1H), 7.42 (dd, J=2.7, 9.3 Hz, 1H), 7.28-7.36 (m, 5H), 5.49 (d, J=9.3Hz, 1H), 5.43 (s, 2H), 5.13 (s, 2H), 2.21 (s, 3H). ESI MS m/z 282[M+H]⁺.

Example 183 Preparation of3-(Azetidin-1-yl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one

Step 1:

To a solution of 38 (3.00 g, 14.4 mmol) in acetonitrile (120 mL) wasadded benzyl bromide (2.95 g, 17.3 mmol) and potassium carbonate (3.97g, 28.8 mmol). The reaction was heated at 75° C. for 17 h. The reactionmixture was cooled to room temperature, concentrated, and purified bychromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 39(3.70 g, 86%) as a light-brown solid: ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d,J=2.5 Hz, 1H), 7.31-7.41 (m, 6H), 5.14 (s, 2H).

Step 2:

To a solution of 39 (3.70 g, 12.4 mmol) in 1,4-dioxane (180 mL) andwater (20 mL) was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(3.47 g, 14.9 mmol), potassium carbonate (3.42 g, 24.8 mmol), andtetrakis(triphenylphosphine)palladium(0) (286 mg, 0.248 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 17 h.The reaction mixture was cooled to room temperature, concentrated, andpurified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) toafford 40 (2.52 g, 65%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ7.42 (d, J=2.3 Hz, 1H), 7.32-7.41 (m, 5H), 7.08 (d, J=2.3 Hz, 1H), 5.22(s, 2H), 2.29 (s, 3H), 2.14 (s, 3H); ESI m/z 315 [M+H]⁺.

Step 3:

To a solution of 40 (100 mg, 0.318 mmol) in toluene (10 mL) undernitrogen atmosphere was added azetidine (36 mg, 0.64 mmol), cesiumcarbonate (208 mg, 0.640 mmol), racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (30 mg, 0.048 mmol), andtris(dibenzylideneacetone) dipalladium(0) (29 mg, 0.018 mmol). Thereaction mixture was heated at 90° C. for 17 h, cooled to roomtemperature, and purified by chromatography (silica gel, 0-50% ethylacetate/hexanes). It was further purified by reverse phase HPLC on aPolaris column eluting with 10-90% CH₃CN in H₂O to give Example 183 (13mg, 12%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.25-7.38(m, 5H), 7.21 (d, J=2.2 Hz, 1H), 6.07 (d, J=2.2 Hz, 1H), 5.07 (s, 2H),3.89 (t, J=7.2 Hz, 4H), 2.34 (s, 3H), 2.18 (t, J=7.2 Hz, 2H), 2.17 (s,3H); ESI m/z 336 [M+H]⁺.

Example 189 Preparation of3-Amino-1-benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one

Step 1:

To a solution of 41 (950 mg, 3.41 mmol) in 1,4-dioxane (40 mL) was addedbis(pinacolato)diboron (1.04 g, 4.09 mmol), potassium acetate (668 mg,6.82 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (125 mg,0.171 mmol). The reaction mixture was heated at 90° C. for 17 h undernitrogen atmosphere. The reaction mixture was cooled to roomtemperature, concentrated, and purified by chromatography (silica gel,0-30% ethyl acetate/hexanes) to give 42 (490 mg, 44%) as an off-whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.23-7.36 (m, 6H), 6.61 (d, J=1.6 Hz,1H), 5.16 (s, 2H), 5.08 (s, 2H), 1.23 (s, 12H).

Step 2:

To a solution of 42 (400 mg, 1.50 mmol) in 1,4-dioxane (20 mL) and water(2 mL) was added (4-iodo-5-methylisoxazol-3-yl)methanol (431 mg, 1.80mmol), potassium carbonate (414 mg, 3.00 mmol), andtetrakis(triphenylphosphine)palladium(0) (86 mg, 0.075 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C.overnight. The reaction mixture was cooled to room temperature,concentrated, and purified by chromatography (silica gel, 0-50% ethylacetate/hexanes). It was further purified by reverse phase HPLC on aPolaris column eluting with 10-90% CH₃CN in H₂O to give Example 189 (150mg, 32%) as a light yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.25-7.37(m, 5H), 7.18 (d, J=2.2 Hz, 1H), 6.57 (d, J=2.2 Hz, 1H), 5.42 (t, J=5.6Hz, 1H), 5.25 (s, 2H), 5.12 (s, 2H), 4.44 (d, J=5.6 Hz, 2H), 2.37 (s,3H); ESI m/z 312 [M+H]⁺.

Example 197 Preparation of1-(4-Chlorobenzyl)-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one

Step 1:

To a solution of 43 (400 mg, 5.5 mmol) in CH₃CN (2 mL) was added 44(0.805 mL, 5.5 mmol). The reaction mixture was heated at 50° C. for 30minutes, then a solution of 45 (621 mg, 5.0 mmol) in CH₃CN (1 mL) andAcOH (3 mL) were added. The reaction mixture was heated at 120° C. for 2h. The mixture was diluted with saturated NaHCO₃ (100 mL), and wasextracted with ethyl acetate (200 mL). The organic layer was dried oversodium sulfate, filtered and concentrated. The residue was trituratedwith ethyl acetate/hexanes to afford 46 (445 mg, 44%) as a light brownsolid: ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J=2.7 Hz, 1H), 7.41 (dd,J=8.7, 2.7 Hz, 1H), 7.00 (dd, J=8.7, 0.6 Hz, 1H), 4.02 (s, 3H), 2.28 (s,6H).

Step 2:

A solution of 46 (198 mg, 0.97 mmol) in EtOH (4 mL) and 48% HBr (2 mL)was heated to reflux for 1 h. The reaction mixture was concentrated todryness to afford 47 (265 mg, 100%) as a brown solid: ¹H NMR (300 MHz,DMSO-d₆) δ 7.94 (d, J=3.0 Hz, 1H), 7.63 (dd, J=9.6, 3.0 Hz, 1H), 6.55(d, J=9.6 Hz, 1H), 2.43 (s, 6H).

Step 3:

To a solution of 47 (55 mg, 0.20 mmol) in acetonitrile (1 mL) and DMF (3mL) was added 4-chlorobenzyl chloride (19 mg, 0.12 mmol) and potassiumcarbonate (83 mg, 0.60 mmol). The reaction was heated at 50° C. for 4 h.The reaction mixture was diluted with ethyl acetate (50 mL) and washedwith brine (50 mL). The organic layer was dried over sodium sulfate,filtered and concentrated. The residue was triturated with ethyl acetateto afford Example 197 (28 mg, 73%) as an off-white solid: ¹H NMR (300MHz, DMSO-d₆) δ 8.30 (d, J=2.7 Hz, 1H), 7.58 (dd, J=9.6, 2.4 Hz, 1H),7.45-7.36 (m, 4H), 6.55 (d, J=9.6 Hz, 1H), 5.08 (s, 2H), 2.19 (s, 6H);ESI m/z 315 [M+H]⁺.

Example 198 Preparation of1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile

A mixture of1-benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one (50 mg,0.16 mmol), KCN (104 mg, 1.6 mmol) and DMSO (3 mL) was heated to 120° C.under nitrogen. The reaction mixture was heated at that temperature for18 hours and then cooled to room temperature. Water (10 mL) was addedand the solution was extracted with ethyl acetate (3×20 mL). Thecombined extracts were dried over sodium sulfate, filtered andconcentrated. The product was purified by silica gel chromatography(eluting with 0 to 50% ethyl acetate in hexanes) to provide Example 198(15 mg, 31%): ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J=2.6 Hz, 1H),7.45-7.33 (m, 6H), 5.21 (s, 2H), 2.28 (s, 3H), 2.13 (s, 3H); ESI MS m/z306 [M+H]⁺.

Examples 229 and 230 Preparation of1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide(Example 230) and1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylicacid (Example 229)

To a solution of1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile(Example 198, 58 mg, 0.19 mmol) and EtOH (2 mL) was slowly added NaOH(2M, 0.5 mL, 0.95 mmol) at room temperature. The solution was heated at80° C. for 3 hours and then cooled back to room temperature. Thesolution was then neutralized with HCl (6N) and extracted with CH₂Cl₂.The organic layer was dried over sodium sulfate, filtered andconcentrated. The products were purified by combiflash (eluting with 0to 5% methanol in CH₂Cl₂) to yield1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylicacid (Example 229) (22 mg, 34%) as the first eluted compound: ¹H NMR(500 MHz, CDCl₃) δ 8.41 (s, 1H), 7.49-7.39 (m, 4H), 7.36-7.33 (m, 2H),5.28 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H); ESI MS m/z 325 [M+H]⁺ and1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide(Example 230) (21 mg, 33%) as the second eluted compound: ¹H NMR (500MHz, CDCl₃) δ 9.55 (s, 1H), 8.45 (d, J=2.7 Hz, 1H), 7.44-7.30 (m, 6H),5.75 (s, 1H), 5.26 (s, 2H), 2.30 (s, 3H), 2.15 (s, 3H); ESI MS m/z 324[M+H]⁺.

Example 200 Preparation ofN-(1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methanesulfonamide

To a solution of 49 (85 mg, 0.29 mmol) and triethylamine (0.12 mL, 0.86mmol) in CH₂Cl₂ (5 mL) at room temperature was added methanesulfonylchloride (37 mg, 0.32 mmol). The reaction was stirred at roomtemperature for 17 h and the mixture was chromatographed on silica gel(40 g) using 0-60% ethyl acetate in hexanes. After concentration, theproduct residue was further purified by reverse phase HPLC on a Polariscolumn eluting with 10-90% CH₃CN in H₂O to give Example 200 (12 mg, 11%)as a white solid: ¹H NMR (500 MHz, DMSO-d₆): δ 9.02 (s, 1H), 7.78 (d,J=3.5 Hz, 1H), 7.38-7.26 (m, 6H), 5.20 (s, 2H), 3.30 (s, 3H), 2.42 (s,3H), 2.20 (s, 3H). ESI MS m/z 374 [M+H]⁺.

Example 201 Preparation of2-Benzyl-6-(((3,5-dimethylisoxazol-4-yl)methyl)amino)pyridazin-3(2H)-one

Step 1:

To a solution of 2 (440 mg, 2.0 mmol) in dioxane (6 mL) was addedacetamide (180 mg, 3.0 mmol), XantPhos (232 mg, 0.4 mmol), cesiumcarbonate (980 mg, 3.0 mmol) and palladium acetate (44 mg, 0.2 mmol).The reaction mixture was purged with nitrogen for 5 min, and then heatedunder nitrogen at 110° C. for 16 h. The reaction mixture was cooled toroom temperature, concentrated and purified by chromatography (silicagel, 0-100% ethyl acetate/hexanes) to give 50 (451 mg, 93%) as a whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J=16.0 Hz, 1H), 7.51 (s, 1H),7.39-7.29 (m, 5H), 7.0 (d, J=16.5 Hz, 1H), 5.21 (s, 2H), 2.16 (s, 3H).

Step 2:

To a solution of 50 (439 mg, 1.8 mmol) in MeOH/water (15 mL/5 mL) wasadded NaOH (360 mg, 9.0 mmol). The reaction mixture was refluxed for 5 hand concentrated. The residue was partitioned between DCM and water, andextracted with DCM. The organic layer was dried over sodium sulfate,filtered and concentrated to give 51 (368 mg, 100%) as a yellow solid:ESI m/z 202 [M+H]⁺.

Step 3:

To a solution of 51 (20 mg, 0.10 mmol) in DMF (1 mL) was added4-(bromomethyl)-3,5-dimethylisoxazole (29 mg, 0.15 mmol) and potassiumcarbonate (28 mg, 0.20 mmol). The reaction was heated at 60° C. for 16h. The reaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-100% ethyl acetate/hexanes) toafford Example 201 (13 mg, 42%) as a white solid: ¹H NMR (300 MHz,DMSO-d₅) δ 7.41-7.38 (m, 2H), 7.35-7.27 (m, 3H), 6.86 (d, J=16.0 Hz,1H), 6.69 (d, J=16.0 Hz, 1H), 5.20 (s, 2H), 4.09 (s, 2H), 2.34 (s, 3H),2.23 (s, 3H); ESI m/z 310 [M+H]⁺.

Examples 199, 202, and 225 Preparation of Methyl4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylate(Example 199),4-(1-(4-Chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxamide(Example 202) and4-(1-(4-Chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylicacid (Example 225)

Step 1:

To a solution of 7 (5.00 g, 28.7 mmol) in acetonitrile (200 mL) wasadded 1-chloro-4-(chloromethyl)benzene (5.55 g, 34.5 mmol) and potassiumcarbonate (7.92 g, 57.4 mmol). The reaction was heated at 75° C. for 2h. The reaction mixture was cooled to room temperature, concentrated,and purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes)to afford 52 (7.32 g, 85%) as an off-white solid: ¹H NMR (500 MHz,CDCl₃) δ 7.20-7.40 (m, 6H), 6.53 (dd, J=1.3, 8.9 Hz, 1H), 5.05 (s, 2H);ESI m/z 298 [M+H]⁺.

Step 2:

To a solution of 52 (4.43 g, 14.5 mmol) in 1,4-dioxane (150 mL) wasadded bis(pinacolato)diboron (4.41 g, 17.4 mmol), potassium acetate(2.84 g, 29.0 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (530 mg,0.725 mmol). The reaction mixture was heated at 100° C. for 17 h undernitrogen atmosphere. The reaction mixture was cooled to roomtemperature, concentrated, and purified by chromatography (silica gel,0-50% ethyl acetate/hexanes) to give 53 (3.72 g, 74%) as an off-whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 7.75 (d, J=1.7 Hz, 1H), 7.60 (dd,J=1.7, 9.1 Hz, 1H), 7.21-7.34 (m, 4H), 6.56 (d, J=9.1 Hz, 1H), 5.10 (s,2H), 1.29 (s, 12H); ESI m/z 346 [M+H]⁺.

Step 3:

To a solution of 53 (1.51 g, 4.36 mmol) in 1,4-dioxane (80 mL) and water(8 mL) was added methyl 4-bromo-5-methylisoxazole-3-carboxylate (800 mg,3.64 mmol), potassium carbonate (1.01 g, 7.28 mmol), andtetrakis(triphenylphosphine)palladium(0) (210 mg, 0.182 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 17 h.The reaction mixture was cooled to room temperature, concentrated andpurified by chromatography (silica gel, 0-50% ethyl acetate/hexanes). Itwas further purified by reverse phase HPLC on a Polaris column elutingwith 10-90% CH₃CN in H₂O to give Example 199 (140 mg, 9%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J=2.3 Hz, 1H),7.50 (dd, J=2.5, 9.3 Hz, 1H), 7.33-7.47 (m, 4H), 6.47 (d, J=9.3 Hz, 1H),5.09 (s, 2H), 3.79 (s, 3H), 2.44 (s, 3H); ESI m/z 359 [M+H]⁺.

Step 4:

To a solution of Example 199 (50 mg, 0.14 mmol) in formamide (4 mL) wasadded potassium tert-butoxide (31 mg, 0.28 mmol). The reaction mixturewas purged with nitrogen and heated in the microwave at 100° C. for 30min. The reaction mixture was cooled to room temperature and treatedwith acetic acid (25 mg, 0.42 mmol). The mixture was purified by reversephase HPLC on a Polaris column eluting with 10-90% CH₃CN in H₂O to giveExample 202 (47 mg, 97%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ8.13 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.82 (s, 1H), 7.45 (dd, J=2.5, 9.3Hz, 1H), 7.34-7.44 (m, 4H), 6.45 (d, J=9.3 Hz, 1H), 5.09 (s, 2H), 2.42(s, 3H); ESI m/z 344 [M+H]⁺.

Step 5:

To a solution of Example 199 (30 mg, 0.083 mmol) in 1,4-dioxane (4 mL)and water (1 mL) was added lithium hydroxide (8 mg, 0.3 mmol). Themixture was stirred at room temperature for 17 h and treated with aceticacid (0.5 mL). The mixture was purified by reverse phase HPLC on aPolaris column eluting with 10-90% CH₃CN in H₂O to give Example 225 (25mg, 87%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.84 (d, J=2.4Hz, 1H), 7.56 (dd, J=2.4, 9.3 Hz, 1H), 7.35 (s, 4H), 6.60 (d, J=9.3 Hz,1H), 5.19 (s, 2H), 2.40 (s, 3H); ESI m/z 345 [M+H]⁺.

Example 205 Preparation of3-Amino-1-(4-chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one

Step 1:

To a solution of 21 (700 mg, 3.70 mmol) in acetonitrile (15 mL) and DMF(5 mL) was added 1-chloro-4-(chloromethyl)benzene (596 mg, 3.70 mmol)and potassium carbonate (1.02 g, 7.40 mmol). The reaction was heated at60° C. for 17 h. The reaction mixture was cooled to room temperature,concentrated, and purified by chromatography (silica gel, 0-50% ethylacetate/hexanes) to afford 54 (990 mg, 85%) as a light-brown solid: ¹HNMR (500 MHz, CDCl₃) δ 7.20-7.36 (m, 4H), 6.80 (d, J=2.3 Hz, 1H), 6.54(d, J=2.3 Hz, 1H), 5.07 (s, 2H), 4.38 (s, 2H).

Step 2:

To a solution of 54 (990 mg, 3.16 mmol) in 1,4-dioxane (40 mL) was addedbis(pinacolato)diboron (1.12 g, 4.42 mmol), potassium acetate (619 mg,6.32 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (115 mg,0.158 mmol). The reaction mixture was heated at 90° C. for 17 h undernitrogen atmosphere. The reaction mixture was cooled to roomtemperature, concentrated, and purified by chromatography (silica gel,0-50% ethyl acetate/hexanes) to give 55 (710 mg, 62%) as an off-whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 7.15-7.35 (m, 5H), 6.78 (d, J=1.6 Hz,1H), 5.10 (s, 2H), 4.12 (s, 2H), 1.28 (s, 12H); ESI m/z 361 [M+H]⁺.

Step 3:

To a solution of 55 (300 mg, 0.832 mmol) in 1,4-dioxane (15 mL) andwater (1.5 mL) was added (4-iodo-5-methylisoxazol-3-yl)methanol (239 mg,0.999 mmol), potassium carbonate (230 mg, 1.66 mmol), andtetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol). Thereaction mixture was purged with nitrogen and heated at 90° C. for 17 h.The reaction mixture was cooled to room temperature, concentrated, andpurified by chromatography (silica gel, 0-50% ethyl acetate/hexanes). Itwas further purified by reverse phase HPLC on a Polaris column elutingwith 10-90% CH₃CN in H₂O to give Example 205 (110 mg, 32%) as a graysolid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.32-7.45 (m, 4H), 7.19 (d, J=2.2 Hz,1H), 6.57 (d, J=2.2 Hz, 1H), 5.43 (t, J=5.6 Hz, 1H), 5.27 (s, 2H), 5.11(s, 2H), 4.44 (d, J=5.6 Hz, 2H), 2.38 (s, 3H); ESI m/z 346 [M+H]⁺.

Example 218 Preparation of5-(3,5-Dimethylisoxazol-4-yl)-1-(4-vinylbenzyl)pyridin-2(1H)-one

To a solution of 14 (150 mg, 0.789 mmol) in acetonitrile (20 mL) wasadded 1-(chloromethyl)-4-vinylbenzene 56 (145 mg, 0.947 mmol) andpotassium carbonate (327 mg, 2.37 mmol). The reaction was heated at 75°C. for 3 h. The reaction mixture was cooled to room temperature,concentrated, and purified by chromatography (silica gel, 0-100% ethylacetate/hexanes). It was further purified by reverse phase HPLC on aPolaris column eluting with 10-90% CH₃CN in H₂O to give Example 218 (180mg, 75%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (d,J=2.4 Hz, 1H), 7.50 (dd, J=2.5, 9.3 Hz, 1H), 7.30-7.50 (m, 4H), 6.71(dd, J=10.9, 17.6 Hz, 1H), 6.51 (d, J=9.3 Hz, 1H), 5.81 (dd, J=0.7, 17.6Hz, 1H), 5.25 (dd, J=0.63, 10.9 Hz, 1H), 5.11 (s, 2H), 2.35 (s, 3H),2.18 (s, 3H); ESI m/z 307 [M+H]⁺.

Example 224 Preparation of3-Amino-5-(3,5-dimethylisoxazol-4-yl)-1-methylpyridin-2(1H)-one

To a mixture of 30 (100 mg, 0.488 mmol) and potassium carbonate (135 mg,0.976 mmol) in acetonitrile (4 mL) at room temperature was added amixture of iodomethane (69 mg, 0.488 mmol) in acetonitrile (1 mL). Themixture was stirred at room temperature overnight, concentrated, andpurified by chromatography (silica gel, 0-100% ethyl acetate/hexanes).It was further purified by reverse phase HPLC on a Polaris columneluting with 10-90% CH₃CN in H₂O to give Example 224 (31 mg, 29%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 6.97 (d, J=2.2 Hz, 1H),6.42 (d, J=2.2 Hz, 1H), 5.22 (s, 2H), 3.47 (s, 3H), 2.35 (s, 3H), 2.18(s, 3H); ESI m/z 220 [M+H]⁺.

Example 237 Preparation of3-Amino-1-(4-(azetidin-1-yl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one

Step 1:

To a solution of 31 (1.38 g, only 50% pure, 2.79 mmol) in acetonitrile(50 mL) was added 57 (1.05 g, 4.19 mmol) and potassium carbonate (1.93g, 14.0 mmol). The reaction was heated at 60° C. for 2 h. The reactionmixture was cooled to room temperature, concentrated, and purified bychromatography (silica gel, 0-100% ethyl acetate/hexanes) to afford 58(1.02 g, 88%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.43(s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.56 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 5.17 (s, 2H), 2.37 (s, 3H), 2.19 (s,3H), 2.11 (s, 3H); ESI m/z 416 [M+H]⁺.

Step 2:

To a solution of 58 (70 mg, 0.17 mmol) in toluene (5 mL) under nitrogenatmosphere was added azetidine (39 mg, 0.68 mmol), cesium carbonate (111mg, 0.340 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene(18 mg, 0.026 mmol), and tris(dibenzylideneacetone) dipalladium(0) (15mg, 0.017 mmol). The reaction mixture was heated at 100° C. for 5 h,cooled to room temperature, and purified by chromatography (silica gel,0-100% ethyl acetate/hexanes) to afford 59 (48 mg, 72%) as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) δ 8.45 (s, 1H), 8.31 (d, J=2.3 Hz, 1H),7.17 (d, J=8.5 Hz, 2H), 6.84 (d, J=2.3 Hz, 1H), 6.41 (d, J=8.5 Hz, 2H),5.08 (s, 2H), 3.87 (t, J=7.2 Hz, 4H), 2.36 (quintet, J=7.2 Hz, 2H), 2.31(s, 3H), 2.20 (s, 3H), 2.17 (s, 3H); ESI m/z 393 [M+H]⁺.

Step 3:

A solution of 59 (48 mg, 0.12 mmol) and LiOH (12 mg, 0.49 mmol) in1,4-dioxane (4 mL) and water (2 mL) was heated at 100° C. for 2 daysunder nitrogen. The reaction mixture was cooled to room temperature,treated with acetic acid (0.5 mL), and concentrated. The residue waspurified by reverse phase HPLC on a Polaris column eluting with 10-90%CH₃CN in H₂O to give Example 237 (32 mg, 76%) as a light yellow solid:¹H NMR (500 MHz, DMSO-d₆) δ 7.23 (d, J=8.5 Hz, 2H), 7.04 (d, J=2.2 Hz,1H), 6.04 (d, J=2.2 Hz, 1H), 6.35 (d, J=8.5 Hz, 2H), 5.23 (s, 2H), 4.98(s, 2H), 3.74 (t, J=7.1 Hz, 4H), 2.33 (s, 3H), 2.26 (quintet, J=7.1 Hz,2H), 2.16 (s, 3H); ESI m/z 351 [M+H]⁺.

Example 238 Preparation of3-Amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-morpholinobenzyl)pyridin-2(1H)-one

Step 1:

To a solution of 60 (450 mg, 2.33 mmol) in chloroform (5 mL) was addedthionyl chloride (1.00 mL). The mixture was heated at 60° C. for 2 h andconcentrated to afford crude 61 (624 mg, >99%) as a yellow solid.

Step 2: To a solution ofN-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide31 (200 mg, 50% pure, 0.405 mmol) in acetonitrile (20 mL) was added 61(201 mg, 0.810 mmol) and potassium carbonate (335 mg, 2.43 mmol). Thereaction was heated at 60° C. for 17 h. The reaction mixture was cooledto room temperature, concentrated, and purified by chromatography(silica gel, 0-100% ethyl acetate/hexanes) to afford 62 (160 mg, 94%) asan off-white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.43 (s, 1H), 8.32 (d,J=2.2 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 6.86 (d,J=2.2 Hz, 1H), 5.12 (s, 2H), 3.84 (t, J=4.9 Hz, 4H), 3.15 (t, J=4.9 Hz,4H), 2.32 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H); ESI m/z 423 [M+H]⁺.

Step 3:

A solution of 62 (100 mg, 0.237 mmol) and LiOH (23 mg, 0.94 mmol) in1,4-dioxane (4 mL) and water (2 mL) was heated at 100° C. for 17 h undernitrogen. The reaction mixture was cooled at room temperature, treatedwith acetic acid (0.5 mL), and concentrated. The residue was purified byreverse phase HPLC on a Polaris column eluting with 10-90% CH₃CN in H₂Oto give Example 238 (65 mg, 72%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 7.27 (d, J=8.7 Hz, 2H), 7.07 (d, J=2.2 Hz, 1H), 6.89 (d,J=8.7 Hz, 2H), 6.41 (d, J=2.2 Hz, 1H), 5.24 (s, 2H), 5.01 (s, 2H), 3.70(t, J=4.8 Hz, 4H), 3.06 (t, J=4.8 Hz, 4H), 2.33 (s, 3H), 2.16 (s, 3H);ESI m/z 381 [M+H]⁺.

Example 241 Preparation of3-Amino-1-(4-bromobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one

A solution of 58 (500 mg, 1.20 mmol) and LiOH (288 mg, 12.0 mmol) in1,4-dioxane (20 mL) and water (5 mL) was heated at 100° C. for 17 hunder nitrogen. The reaction mixture was cooled to room temperature,concentrated, and purified by chromatography (silica gel, 0-100% ethylacetate/hexanes) to give Example 241 (360 mg, 80%) as a yellow solid: ¹HNMR (500 MHz, DMSO-d₆) δ 7.54 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H),7.11 (d, J=2.2 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H), 5.27 (s, 2H), 5.10 (s,2H), 2.34 (s, 3H), 2.17 (s, 3H); ESI m/z 374 [M+H]⁺.

Example 243 Preparation of1-(4-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-((2,2,2-trifluoroethyl)amino)pyridin-2(1H)-one

A mixture of Example 152 (50 mg, 0.15 mmol) and cesium carbonate (98 mg,0.30 mmol) in 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 mL)was heated at 120° C. for 8 h. The reaction mixture was cooled to roomtemperature, concentrated, and purified by chromatography (silica gel,0-50% ethyl acetate/hexanes). It was further purified by reverse phaseHPLC on a Polaris column eluting with 10-90% CH₃CN in H₂O to giveExample 243 (31 mg, 50%) as an off-white solid: ¹H NMR (500 MHz,DMSO-d₆) δ 7.36-7.45 (m, 4H), 7.23 (d, J=2.1 Hz, 1H), 6.55 (d, J=1.7 Hz,1H), 6.11 (t, J=7.1 Hz, 1H), 5.14 (s, 2H), 3.93-4.04 (m, 2H), 2.35 (s,3H), 2.18 (s, 3H); ESI m/z 412 [M+H]⁺.

Example 247 Preparation of1-((1H-Indol-4-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one

Step 1:

To a solution of 31 (700 mg, 2.83 mmol), (1H-indol-4-yl)methanol (1.25g, 8.50 mmol), and triphenylphosphine (2.97 g, 11.3 mmol) intetrahydrofuran (30 mL) at 60° C. under nitrogen atmosphere was addeddiisopropyl azodicarboxylate (1.43 g, 7.07 mmol). The mixture was cooledto room temperature, concentrated, and purified by chromatography(silica gel, 0-100% ethyl acetate/hexanes) to give crude 59 (1.94 g,contained Ph₃PO).

Step 2:

A solution of crude 59 (1.94 g, 5.16 mmol) and LiOH (1.24 g, 51.6 mmol)in 1,4-dioxane (30 mL) and water (30 mL) was heated at 100° C. for 17 hunder nitrogen atmosphere. The reaction mixture was cooled to roomtemperature, concentrated and purified by chromatography (silica gel,0-100% ethyl acetate/hexanes). It was further purified by reverse phaseHPLC on a Polaris column eluting with 10-90% CH₃CN in H₂O to giveExample 247 (285 mg, 30% over 2 steps) as an off-white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 11.17 (s, 1H), 7.31-7.36 (m, 2H), 7.03 (t, J=7.3Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 6.87 (d, J=7.0 Hz, 1H), 6.59-6.62 (m,1H), 6.43 (d, J=2.3 Hz, 1H), 5.40 (s, 2H), 5.28 (s, 2H), 2.25 (s, 3H),2.08 (s, 3H); ESI m/z 335 [M+H]⁺.

Example 266 Preparation of3-(Aminomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one

Step 1:

A mixture of 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid 60 (10g, 45.9 mmol), H₂SO₄, and EtOH (225 mL) was heated at reflux for 1 hour.The solution was cooled to room temperature and concentrated. Theresidue was taken up in CH₂Cl₂ (200 mL) and washed with saturated sodiumbicarbonate solution, dried over sodium sulfate and filtered. Thesolvent was removed and purified by silica gel chromatography (0 to 5%methanol in CH₂Cl₂) to provide compound 61 (8 g, 71%).

Step 2:

To a mixture of LiAlH₄ (300 mg, 7.93 mmol) and THF (40 mL) at 0° C.under nitrogen was slowly added a solution of ethyl5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate 61 (1.5 g, 6.09 mmol)and THF (20 mL). After 2.5 hours, the reaction was quenched by slowaddition of water. The resultant solid was removed by filtration and thefiltrate was extracted with CH₂Cl₂ (2×100 mL). The combined extractswere dried over sodium sulfate and filtered. The solvent was removedunder reduced pressure to provide compound 62 (380 mg, 28%).

Step 3:

To a suspension of 5-bromo-3-(hydroxymethyl)pyridin-2(1H)-one 62 (350mg, 1.72 mmol), Et₃N (0.71 mL, 5.16 mmol) and CH₂Cl₂ (15 mL) was slowlyadded methanesulfonyl chloride (0.27 mL, 3.43 mmol) at 0° C. undernitrogen. The reaction mixture was allowed to warm to room temperaturefor 17 h and then water was added. The layers were separated and theaqueous was extracted with CH₂Cl₂. The organic phase was dried oversodium sulfate and filtered. The solvent was removed and the residue waspurified by silica gel chromatography (eluting with 0 to 30% ethylacetate in hexanes) to provide compound 63 (75 mg, 15%).

Step 4:

To a solution of (5-bromo-2-oxo-1,2-dihydropyridin-3-yl)methylmethanesulfonate 63 (75 mg, 0.27 mmol), and DMF (5 mL) was added sodiumazide at room temperature. The mixture was stirred for 18 hours undernitrogen. The solvent was removed under reduced pressure and the residuewas partitioned between water (20 mL) and ethyl acetate (20 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (20 mL). The organic layers were combined and dried over sodiumsulfate and filtered. The solvent was removed under reduced pressure andthe product was purified by silica gel chromatography (eluting with 0 to70% ethyl acetate in hexanes) to provide compound 64 (34 mg, 55%).

Step 5:

To a mixture of 3-(azidomethyl)-5-bromopyridin-2(1H)-one 64 (34 mg, 0.15mmol), K₂CO₃ (42 mg, 0.30 mmol) and CH₃CN (5 mL) was added benzylbromide (30 mg, 0.18 mmol) at room temperature. The reaction mixture wasstirred for 18 hours and then diluted with CH₂Cl₂. The mixture waswashed with water, dried over sodium sulfate and filtered. The solventwas removed under reduced pressure and the product was purified bysilica gel chromatography (eluting with 0 to 50% ethyl acetate inhexanes) to provide compound 65 (30 mg, 63%).

Step 6:

A mixture of 3-(azidomethyl)-1-benzyl-5-bromopyridin-2(1H)-one 65 (30mg, 0.09 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoxazole(32 mg, 0.14 mmol), K₂CO₃ (25 mg, 0.18 mmol),tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), H₂O (0.5mL) and dioxane (3 mL) was heated at 90° C. under nitrogen for 18 hours.The mixture was cooled to room temperature and adsorbed onto silica gel.The product was purified by silica gel chromatography (eluting with 0 to50% ethyl acetate in hexanes) to provide compound 66 (9 mg, 30%).

Step 7:

To a solution of3-(azidomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one66 (9 mg, 0.03 mmol) and THF (1 mL) was added trimethylphosphine (1.0Min THF, 0.1 mL, 0.1 mmol) at room temperature. The mixture was heated to60° C. for 1 hour and then concentrated. The product was purified bysilica gel chromatography (eluting with 0 to 25% CMA (80% CH₂Cl₂, 18%methanol, 2% NH₄OH) in CH₂Cl₂) to provide Example 266 (6 mg, 67%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.27 (m, 6H), 7.10 (d, J=2.5Hz, 1H), 5.19 (s, 2H), 3.89 (s, 3H), 2.31 (s, 3H), 2.15 (s, 3H); ESI MSm/z 310 [M+H]⁺.

Example 268 Preparation of1-Benzyl-5-(5-oxopyrrolidin-3-yl)pyridin-2(1H)-one

Step 1:

A solution of 67 (1.37 g, 10.0 mmol) and 68 (3.34 g, 10.0 mmol) inmethylene chloride (30 mL) was stirred at rt for 16 h. The reactionmixture was concentrated and the residue was purified by chromatography(silica gel, 0-30% ethyl acetate/hexanes) to afford 69 (1.75 g, 90%) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.27 (d, J=2.4 Hz, 1H), 7.77(dd, J=8.7, 2.4 Hz, 1H), 7.65 (d, J=15.9 Hz, 1H), 6.77 (d, J=8.7 Hz,1H), 6.34 (d, J=15.9 Hz, 1H), 3.97 (s, 3H), 3.81 (s, 3H).

Step 2:

To a solution of 69 (280 mg, 1.45 mmol) in CH₃NO₂ (10 mL), DBU (0.24 mL,1.60 mmol) was added at 0° C. The reaction mixture was stirred at 0° C.for 5 minutes, then warmed to rt for 4 h. The reaction mixture wasdiluted with ethyl acetate (100 mL) and washed with brine (50 mL). Theorganic layer was dried over sodium sulfate, filtered and concentrated.The residue was purified by chromatography (silica gel, 0-30% ethylacetate/hexanes) to afford 70 (307 mg, 83%) as a colorless oil: ¹H NMR(300 MHz, CDCl₃) δ 8.06 (d, J=2.4 Hz, 1H), 7.44 (dd, J=8.7, 2.4 Hz, 1H),6.73 (d, J=8.7 Hz, 1H), 4.73 (dd, J=12.6, 6.9 Hz, 1H), 4.61 (dd, J=12.6,8.1 Hz, 1H), 4.00-3.90 (m, 4H), 3.65 (s, 3H), 2.83-2.68 (m, 2H).

Step 3:

To a solution of 70 (305 mg, 1.20 mmol) in ethyl acetate (15 mL) wasadded SnCl₂ (1.08 g, 4.80 mmol) and the reaction mixture was heated toreflux for 5 h. The mixture was diluted with ethyl acetate (100 mL) andfiltered. The filtrate was washed with saturated NaHCO₃ (100 mL). Theorganic layer was discarded; the aqueous layer was extracted withCHCl₃/i-PrOH (9/1) (4×50 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated. The residue wasdissolved in MeOH (8 mL) and K₂CO₃ was added. The reaction mixture washeated to reflux for 2 h. The mixture was concentrated, the residue wassuspended in methylene chloride (15 mL) and then filtered. The filtratewas concentrated to dryness to afford 71 (90 mg, 32%) as an off-whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d, J=2.4 Hz, 1H), 7.50 (dd,J=8.4, 2.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.53 (br s, 1H), 3.93 (s,3H), 3.81-3.62 (m, 2H), 3.36 (dd, J=8.7, 6.6 Hz, 1H), 2.73 (dd, J=16.8,8.7 Hz, 1H), 2.43 (dd, J=16.8, 8.7 Hz, 1H).

Step 4:

A mixture of 71 (50 mg, 0.26 mmol) and benzyl bromide (0.062 mL) washeated to 120° C. for 3 h. The reaction mixture was purified bychromatography (silica gel, 0-10% methanol/methylene chloride) to affordExample 268 (15 mg, 21%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃)δ 7.39-7.26 (m, 6H), 7.10 (d, J=2.7 Hz, 1H), 6.67 (d, J=9.6 Hz, 1H),5.63 (br s, 1H), 5.13 (s, 2H), 3.66 (dd, J=9.3, 9.0 Hz, 1H), 3.46-3.38(m, 1H), 3.25 (dd, J=9.3, 7.2 Hz, 1H), 2.61 (dd, J=16.8, 9.0 Hz, 1H),2.30 (dd, J=9.3, 8.7 Hz, 1H); ESI m/z 269 [M+H]⁺.

TABLE 1 Exemplary Embodiments prepared using methods described above.Example Chemical General Number Name Structure Procedure Analytical Data1 6-(3,5- dimethyl- isoxazol-4- yl)-2- phenethyl- pyridazin- 3(2H)-one

C 1H NMR (500 MHz, CDCl3): d 7.30-7.25 (m, 3H), 7.23-7.20 (m, 3H), 7.00(d, J = 9.5 Hz, 1H), 4.54 (t, J = 7.5 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H),2.41 (s, 3H), 2.27 (s, 3H). ESI MS m/z 296 [M + H]+. 2 6-(3,5- dimethyl-isoxazol-4- yl)-2- (pyridin-2- ylmethyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, CDCl3): d 8.56 (d, J = 4.5 Hz, 1H), 7.66 (t, J = 7.5Hz, 1H), 7.32 (d, J = 10 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.23-7.19(m, 1H), 7.06 (d, J = 10 Hz, 1H), 5.52 (s, 2H), 2.45 (s, 3H), 2.28 (s,3H). ESI MS m/z 283 [M + H]+. 3 6-(3,5- dimethyl- isoxazol-4- yl)-2-(pyrimidin- 2-ylmethyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, CDCl3): d 8.69 (d, J = 5.0 Hz, 2H), 7.36 (d, J = 9.5Hz, 1H), 7.20 (t, J = 5.0 Hz, 1H), 7.08 (d, J = 9.5 Hz, 1H), 5.64 (s,2H), 2.47 (s, 3H), 2.30 (s, 3H). ESI MS m/z 284 [M + H]+. 4 5-(3,5-dimethyl- isoxazol-4- yl)-1-(3- (trifluoro- methyl) benzyl) pyridin-2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): d 8.02 (d, J = 2.5 Hz, 1H), 7.76 (s, 1H),7.68-7.52 (m, 3H), 7.50 (d, J = 3.0 Hz, 1H), 6.52 (d, J = 9.5 Hz, 1H),5.21 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 349 [M + H]+. 55-(3,5- dimethyl- isoxazol-4- yl)-1-(4- (trifluoro- methoxy) benzyl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): d 7.95 (d, J = 2.5 Hz, 1H), 7.53-7.45 (m,3H), 7.36 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 9.5 Hz, 1H), 5.21 (s, 2H),2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 365 [M + H]+. 6 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)pyrazin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): d 8.14 (d, J = 1.0 Hz, 1H), 7.95 (d, J =1.0 Hz, 1H), 7.42-7.30 (m, 5H), 5.14 (s, 2H), 2.24 (s, 3H), 2.26 (s,3H). ESI MS m/z 282 [M + H]+. 7 5-(3,5- dimethyl- isoxazol-4- yl)-1-(4-(trifluoro- methyl) benzyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.98 (d, J = 2.5 Hz, 1H), 7.73 (d, J =8.0 Hz, 2H), 7.56-7.51 (m, 3H), 6.53 (d, J = 9.0 Hz, 1H), 5.23 (s, 2H),2.37 (s, 3H), 2.20 (s, 3H). ESI MS m/z 349 [M + H]+. 8 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)pyrimidin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 8.64 (d, J = 3.0 Hz, 1H), 8.50 (d, J =3.0 Hz, 1H), 7.40-7.34 (m, 5H), 5.10 (s, 2H), 2.39 (s, 3H), 2.21 (s,3H). ESI MS m/z 282 [M + H]+. 9 1-(4- ((dimethyl- amino) methyl)benzyl)-5- (3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

G 1H NMR (500 MHz, DMSO-d6): δ 10.17 (br s, 1H), 7.94 (d, J = 2.5 Hz,1H), 7.53-7.50 (m, 3H), 7.42 (d, J = 8.2 Hz, 2H), 6.52 (d, J = 9.4 Hz,1H), 5.17 (s, 2H), 4.24 (d, J = 5.5 Hz, 2H), 2.68 (s, 3H), 2.67 (s, 3H),2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 338 [M + H]+. 10 5-(3,5-dimethyl- isoxazol- 4-yl)-1- (piperidin-4- ylmethyl) pyridin- 2(1H)-one

G 1H NMR (500 MHz, DMSO-d6): δ 8.69 (br d, J = 7.0 Hz, 1H), 8.42 (br s,1H), 7.76 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 9.3, 2.5 Hz, 1H), 6.49 (d,J = 9.3 Hz, 1H), 3.86 (d, J = 7.1 Hz, 2H), 3.27-3.25 (m, 2H), 2.84-2.82(m, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 2.15-2.03 (m, 1H), 1.71- 1.69 (m,2H), 1.43-1.40 (m, 2H). ESI MS m/z 288 [M + H]+. 11 5-(3,5- dimethyl-isoxazol-4- yl)-1-((3,5- dimethyl- isoxazol-4- yl)methyl) pyridin-2(1H)-one

G 1H NMR (500 MHz, CDCl3): δ 7.23 (dd, J = 9.4, 2.5 Hz, 1H), 7.04 (d, J= 2.4 Hz, 1H), 6.67 (d, J = 9.4 Hz, 1H), 4.91 (s, 2H), 2.48 (s, 3H),2.32 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H). ESI MS m/z 300 [M + H]+. 121-benzyl-5- (3,5- dimethyl- isoxazol- 4-yl)-4- methyl- pyridin-2(1H)-one

G 1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 7.00 (s, 1H), 6.56 (s,1H), 5.15 (s, 2H), 2.20 (s, 3H), 2.05 (s, 3H), 1.95 (s, 3H). ESI MS m/z295 [M + H]+. 13 4-((5-(3,5- dimethyl- isoxazol- 4-yl)-2- oxopyridin-1(2H)- yl)methyl) benzamide

G 1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 2.5 Hz, 1H), 7.93 (s, 1H),7.84 (d, J = 8.3 Hz, 2H), 7.51 (dd, J = 9.4, 2.5 hz, 1H), 7.39 (d, J =8.3 Hz, 2H), 7.33 (s, 1H), 6.52 (d, J = 9.4 Hz, 1H), 5.18 (s, 2H), 2.36(s, 3H), 2.19 (s, 3H). ESI MS m/z 324 [M + H]+. 14 2-benzyl-6- (3,5-dimethyl- isoxazol- 4-yl) pyridazin- 3(2H)-one

A 1H NMR (300 MHz, CDCl3) δ 7.48-7.40 (m, 2H), 7.40-7.27 (m, 4H), 7.02(d, J = 9.6 Hz, 1H), 5.36 (s, 2H), 2.46 (s, 3H), 2.32 (s, 3H); ESI m/z282 [M + H]+. 15 3-((6-oxo-3- (3,4,5- trimethoxy- phenyl) pyridazin-1(6H)- yl)methyl) benzonitrile

C 1H NMR (300 MHz, CDCl3) δ 7.78-7.70 (m, 2H), 7.67 (d, J = 9.6 Hz, 1H),7.63-7.57 (m, 1H), 7.46 (q, J = 7.8 Hz, 1H), 7.04 (d, J = 9.9 Hz, 1H),6.96 (s, 2H), 5.42 (s, 2H), 3.94 (s, 6H), 3.90 (s, 3H); ESI m/z 378 [M +H]+. 16 4-((6-oxo- 3-(3,4,5- trimethoxy- phenyl) pyridazin- 1(6H)-yl)methyl) benzonitrile

C 1H NMR (300 MHz, CDCl3) δ 7.70-7.60 (m, 3H), 7.58-7.52 (m, 2H), 7.04(d, J = 9.9 Hz, 1H), 6.95 (s, 2H), 5.44 (s, 2H), 3.93 (s, 6H), 3.09 (s,3H); ESI m/z 378 [M + H]+. 17 N-(3-((6- oxo-3-(3,4,5- trimethoxy-phenyl) pyridazin- 1(6H)- yl)methyl) phenyl) acetamide

C 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.15 (d, J = 9.9 Hz, 1H),7.63 (s, 1H), 7.49 (d, J = 9.3 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.16(s, 2H), 7.09 (d, J = 9.6 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 5.28 (s,2H), 3.85 (s, 6H), 3.70 (s, 3H), 2.00 (s, 3H); ESI m/z 410 [M + H]+. 185-(3,5- dimethyl- isoxazol-4- yl)-1- (quinoxalin- 6-ylmethyl) pyridin-2(1H)-one

E 1H NMR (500 MHz, CDCl3) δ 8.86-8.85 (m, 2H); 8.15-8.11 (m, 1H), 7.96(d, J = 1.2 Hz, 1H); 7.98 (dd, J = 9.5, 2.0 Hz, 1H); 7.29 (dd, J = 9.5,2.5 Hz, 1H); 7.23 (d, J = 2.3 Hz, 1H); 6.75 (d, J = 9.5 Hz, 1H); 5.43(s, 2H); 2.32 (s, 3H); 2.18 (s, 3H); ESI MS m/z 333 [M + H]+. 19 6-(3,5-dimethyl- isoxazol-4- yl)-2-(1- phenylethyl) pyridazin- 3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.6 Hz, 1H), 7.38-7.22 (m,5H), 7.06 (d, J = 9.6 Hz, 1H), 6.27 (q, J = 7.5 Hz, 1H), 2.46 (s, 3H),2.25 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ESI m/z 296 [M + H]+. 202-benzyl-4- methyl-6-(5- methyl- isoxazol- 4-yl) pyridazin- 3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 8.98 (d, J = 0.6 Hz, 1H), 7.76 (d, J = 1.2Hz, 1H), 7.40-7.24 (m, 5H), 5.29 (s, 2H), 2.59 (d, J = 0.3 Hz, 3H), 2.15(d, J = 1.2 Hz, 3H); ESI m/z 282 [M + H]+. 21 2-benzyl-6- (3,5-dimethyl- isoxazol-4- yl)-4- methyl- pyridazin- 3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 7.56 (d, J = 1.5 Hz, 1H), 7.38-7.25 (m,5H), 5.30 (s, 2H), 2.47 (s, 3H), 2.26 (s, 3H), 2.16 (d, J = 1.2 Hz, 3H);ESI m/z 296 [M + H]+. 22 6-(3,5- dimethyl- isoxazol-4- yl)-2-(3-fluorobenzyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J = 9.6 Hz, 1H), 7.46-7.35 (m,1H), 7.22-7.06 (m, 4H), 5.31 (s, 2H), 2.47 (s, 3H), 2.26 (s, 3H); ESIm/z 300 [M + H]+. 23 2-(3- chloro- benzyl)- 6-(3,5- dimethyl-isoxazol-4- yl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J = 9.6 Hz, 1H), 7.46-7.28 (m,4H), 7.11 (d, J = 9.6 Hz, 1H), 5.30 (s, 2H), 2.47 (s, 3H), 2.26 (s, 3H);ESI m/z 316 [M + H]+. 24 2-((3-(3,5- dimethyl- isoxazol-4- yl)-6- oxo-pyridazin- 1(6H)-yl) methyl) benzonitrile

C 1H NMR (300 MHz, DMSO-d6) δ 7.93-7.85 (m, 1H), 7.76-7.64 (m, 2H),7.57-7.46 (m, 2H), 7.13 (d, J = 9.6 Hz, 1H), 5.49 (s, 2H), 2.43 (s, 3H),2.18 (s, 3H); ESI m/z 307 [M + H]+. 25 2-(4- chloro- benzyl)- 6-(3,5-dimethyl- isoxazol-4- yl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J = 9.6 Hz, 1H), 7.48-7.34 (m,4H), 7.09 (d, J = 9.9 Hz, 1H), 5.29 (s, 2H), 2.47 (s, 3H), 2.26 (s, 3H);ESI m/z 316 [M + H]+. 26 2-(2- chloro- benzyl)- 6-(3,5- dimethyl-isoxazol-4- yl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J = 9.9 Hz, 1H), 7.53-7.47 (m,1H), 7.40-7.25 (m, 3H), 7.13 (d, J = 9.6 Hz, 1H), 5.39 (s, 2H), 2.38 (s,3H), 2.12 (s, 3H); ESI m/z 316 [M + H]+. 27 5-(3,5- dimethyl-isoxazol-4- yl)-1-(2- fluorobenzyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.88 (d, J = 2.4 Hz, 1H), 7.54 (dd, J =9.3 Hz, 2.7 Hz, 1H), 7.41- 7.30 (m, 1H), 7.29-7.14 (m, 3H), 6.51 (d, J =9.3 Hz, 1H), 5.18 (s, 2H), 2.20 (s, 3H), 1.99 (s, 3H); ESI m/z 299 [M +H]+. 28 6-(3,5- dimethyl- isoxazol-4- yl)-2-(2- methyl- benzyl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J = 9.0 Hz, 1H), 7.25-7.06 (m,5H), 5.31 (s, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 2.15 (s, 3H); ESI m/z 296[M + H]+. 29 6-(3,5- dimethyl- isoxazol-4- yl)-2-(4- methyl- benzyl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J = 9.6 Hz, 1H), 7.28-7.04 (m,5H), 5.25 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); ESI m/z 296[M + H]+. 30 6-(3,5- dimethyl- isoxazol-4- yl)-2-(3- methyl- benzyl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) ? 7.66 (d, J = 9.6 Hz, 1H), 7.28-7.04 (m,5H), 5.25 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); ESI m/z 296[M + H]+. 31 6-(3,5- dimethyl- isoxazol-4- yl)-2-(3- (trifluoro- methyl)benzyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.58 (m, 5H), 7.11 (d, J = 9.6 Hz,1H), 5.40 (s, 2H), 2.46 (s, 3H), 2.24 (s, 3H); ESI m/z 350 [M + H]+. 326-(3,5- dimethyl- isoxazol-4- yl)-2-(3- fluoro-5- methyl- benzyl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J = 9.6 Hz, 1H), 7.10 (d, J = 9.6Hz, 1H), 7.04-6.92 (m, 3H), 5.26 (s, 2H), 2.47 (s, 3H), 2.29 (s, 3H),2.26 (s, 3H); ESI m/z 314 [M + H]+. 33 6-(3,5- dimethyl- isoxazol-4-yl)-2-(4- methoxy- benzyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.64 (d, J = 9.6 Hz, 1H), 7.31 (d, J = 8.8Hz, 2H), 7.06 (d, J = 9.6 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 5.22 (s,2H), 3.72 (s, 3H), 2.47 (s, 3H), 2.27 (s, 3H); ESI m/z 312 [M + H]+. 346-(3,5- dimethyl- isoxazol-4- yl)-2-(1-(2- (trifluoro- methyl) phenyl)ethyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.78-7.61 (m, 4H), 7.53 (t, J = 7.5 Hz,1H), 7.04 (d, J = 9.9 Hz, 1H), 6.41 (q, J = 6.9 Hz, 1H), 2.40 (s, 3H),2.15 (s, 3H), 1.72 (d, J = 6.9 Hz, 3H); ESI m/z 364 [M + H]+. 35 6-(3,5-dimethyl- isoxazol-4- yl)-2-(3- methoxy- benzyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J = 9.6 Hz, 1H), 7.27 (t, J = 7.8Hz, 1H), 7.09 (d, J = 9.6 Hz, 1H), 6.94-6.84 (m, 3H), 5.26 (s, 2H), 3.73(s, 3H), 2.47 (s, 3H), 2.27 (s, 3H); ESI m/z 312 [M + H]+. 36 6-(3,5-dimethyl- isoxazol-4- yl)-2-(3- (trifluoro- methoxy) benzyl) pyridazin-3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J = 9.6 Hz, 1H), 7.48 (t, J = 7.8Hz, 1H), 7.41-7.28 (m, 3H), 7.11 (d, J = 9.6 Hz, 1H), 5.35 (s, 2H), 2.46(s, 3H), 2.24 (s, 3H); ESI m/z 366 [M + H]+. 37 6-(3,5- dimethyl-isoxazol-4- yl)-2- ((tetrahydro- 2H-pyran-4- yl)methyl) pyridazin-3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.6 Hz, 1H), 7.05 (d, J = 9.6Hz, 1H), 4.00 (d, J = 7.5 Hz, 2H), 3.90-3.78 (m, 2H), 3.30-3.19 (m, 2H),2.49 (s, 3H), 2.32 (s, 3H), 2.24-2.05 (m, 1H), 1.50-1.43 (m, 2H), 1.37-1.20 (m, 2H); ESI m/z 290 [M + H]+. 38 5-(3,5- dimethyl- isoxazol-4-yl)-1-(1-(2- (trifluoro- methyl) phenyl) ethyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.85-7.66 (m, 3H), 7.63-7.54 (m, 1H),7.52-7.47 (m, 2H), 6.48 (d, J = 10.2 Hz, 1H), 6.36-6.25 (s, 1H), 2.23(s, 3H), 2.06 (s, 3H), 1.72 (d, J = 6.9 Hz, 3H); ESI m/z 363 [M + H]+.39 6-(3,5- dimethyl- isoxazol-4- yl)-2-(2- (trifluoro- methoxy) benzyl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J = 9.6 Hz, 1H), 7.53-7.33 (m,4H), 7.12 (d, J = 9.9 Hz, 1H), 5.38 (s, 2H), 2.39 (s, 3H), 2.12 (s, 3H);ESI m/z 366 [M + H]+. 40 5-(3,5- dimethyl- isoxazol-4- yl)-1-(2-(trifluoro- methoxy) benzyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J = 2.4 Hz, 1H), 7.56 (dd, J =9.3 Hz, 2.7 Hz, 1H), 7.50- 7.34 (m, 3H), 7.13 (d, J = 7.5 Hz, 1H), 6.54(d, J = 9.3 Hz, 1H), 5.22 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z365 [M + H]+. 41 5-(3,5- dimethyl- isoxazol-4- yl)-1-(4- methylbenzyl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) ? 7.91 (d, J = 2.4 Hz, 1H), 7.48 (dd, J =9.5 Hz, 2.4 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H),6.49 (d, J = 9.3 Hz, 1H), 5.07 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.18(s, 3H); ESI m/z 295 [M + H]+. 42 5-(3,5- dimethyl- isoxazol-4-yl)-1-(3- fluorobenzyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) ? 7.96 (d, J = 2.1 Hz, 1H), 7.52 (dd, J =6.6 Hz, J2 = 2.7 Hz, 1H), 7.46-7.36 (m, 1H), 7.24- 7.06 (m, 3H), 7.96(d, J = 2.1 Hz, 1H), 5.14 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z299 [M + H]+. 43 5-(3,5- dimethyl- isoxazol-4- yl)-1-(1- phenylpropyl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) ? 7.71 (d, J = 2.4 Hz, 1H), 7.48-7.26 (m,6H), 6.51 (d, J = 9.6 Hz, 1H), 6.00 (t, J = 8.1 Hz, 1H), 2.30-2.17 (m,5H), 2.12 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H); ESI m/z 309 [M + H]+. 445-(3,5- dimethyl- isoxazol-4- yl)-1- (pyridin-3- ylmethyl) pyridin-2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J = 1.5 Hz, 1H), 8.50 (dd, J =4.8 Hz, 1.8 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.77 (dt, J = 7.8 Hz, 2.1Hz, 1H), 7.52 (dd, J = 9.3 Hz, 2.7 Hz, 1H), 7.43-7.35 (m, 1H), 6.51 (d,J = 9.3 Hz, 1H), 5.16 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H); ESI m/z 282[M + H]+. 45 2- (cyclopropyl- methyl)-6- (3,5- dimethyl- isoxazol-4-yl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J = 9.6 Hz, 1H), 7.05 (d, J = 9.6Hz, 1H), 3.97 (d, J = 7.2 Hz, 2H), 2.43 (s, 3H), 2.33 (s, 3H), 1.36-1.19(m, 1H), 0.57-0.47 (m, 2H), 0.42-0.33 (m, 2H); ESI m/z 246 [M + H]+. 465-(3,5- dimethyl- isoxazol-4- yl)-1-((6- methyl- pyridin-2- yl)methyl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.89 (d, J = 2.4 Hz, 1H), 7.66 (t, J = 9.0Hz, 1H), 7.53 (dd, J = 9.3 Hz, 2.7 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H),7.00 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 9.3 Hz, 1H), 5.17 (s, 2H), 2.43(s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 296 [M + H]+. 47 5-(3,5-dimethyl- isoxazol-4- yl)-1- (quinolin-8- ylmethyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 9.01 (dd, J = 4.2 Hz, 1.8 Hz, 1H), 8.44(dd, J = 8.2 Hz, 1.5 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.96 (dd, J =8.7 Hz, 1.4 Hz, 1H), 7.66-7.51 (m, 3H), 7.42 (d, J = 7.3 Hz, 1H), 6.55(d, J = 9.6 Hz, 1H), 5.75 (s, 2H), 2.33 (s, 3H), 2.17 (s, 3H); ESI m/z332 [M + H]+. 48 1- (cyclopropyl- methyl)-5- (3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J = 2.4 Hz, 1H), 7.48 (dd, J =9.6 Hz, 2.4 Hz, 1H), 6.48 (d, J = 9.6 Hz, 1H), 3.77 (d, J = 7.2 Hz, 2H),2.38 (s, 3H), 2.21 (s, 3H), 1.32- 1.18 (m, 1H), 0.57-0.35 (m, 4H); ESIm/z 245 [M + H]+. 49 1- (cyclobutyl- methyl)-5- (3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

G 1H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J = 2.1 Hz, 1H), 7.45 (dd, J =9.3 Hz, 2.7 Hz, 1H), 6.46 (d, J = 9.0, 1H), 3.95 (d, J = 7.5 Hz, 2H),2.77-2.64 (m, 1H), 2.36 (s, 3H), 2.19 (s, 3H), 2.01-1.71 (m, 6H); ESIm/z 259 [M + H]+. 50 1-(3- (difluoro- methyl) benzyl)-5- (3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

G 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J = 2.1 Hz, 1H),7.57 (s, 1H),7.55-7.47 (m, 4H), 7.04 (q, J = 55.8, 1H), 6.52 (d, J = 9.3 Hz, 1H),5.19 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z 331 [M + H]+. 515-(3,5- dimethyl- isoxazol-4- yl)-1-(2- phenoxy- ethyl) pyridin-2(1H)-one

G 1H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J = 2.4 Hz, 1H), 7.50 (dd, J =10.8 Hz, 2.4 Hz, 1H), 7.27 (q, J = 8.4, 2H), 6.97-6.87 (m, 3H), 6.50 (d,J = 9.3 Hz, 1H), 4.29 (dd, J = 14.1 Hz, 4.5 Hz, 4H), 2.37 (s, 3H), 2.20(s, 3H); ESI m/z 311 [M + H]+. 52 1-benzyl-5- (3,4,5- trimethoxy-phenyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J = 2.4, 9.6 Hz, 1H); 7.41 (d, J =2.1 Hz, 1H); 7.33-7.37 (m, 5H); 6.72 (d, J = 9.6 Hz, 1H); 6.51 (s, 2H);5.23 (s, 2H); 3.88 (s, 6H); 3.85 (s, 3H); ESI MS m/z 352 [M + H]+. 532-((2-oxo-5- (3,4,5- trimethoxy- phenyl) pyridin- 1(2H)- yl)methyl)benzonitrile

D 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 2.4 Hz, 1H); 7.58-7.76 (m, 4H);7.41-7.46 (m, 1H); 6.68 (d, J = 9.6 Hz, 1H); 6.64 (s, 2H); 5.38 (s, 2H);3.91 (s, 6H); 3.87 (s, 3H); ESI MS m/z 377 [M + H]+. 54 2-benzyl-6-((3,4,5- trimethoxy- phenyl) amino) pyridazin- 3(2H)-one

B 1H NMR (300 MHz, CDCl3) δ 7.29-7.42 (m, 5H); 6.92 (s, 2H); 6.59 (s,2H); 6.02 (s, 1H); 5.26 (s, 2H); 3.80 (s, 3H); 3.74 (s, 6H); ESI MS m/z368 [M + H]+. 55 1-((5- chloro- pyridin- 2-yl)methyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

G 1H NMR (300 MHz, DMSO-d6) δ 8.57 (dd, J = 2.6 Hz, 0.6 Hz, 1H), 7.93(dd, J = 8.3 Hz, 2.4 Hz, 1H), 7.88 (d, J = 5.0 Hz, 1H), 7.54 (dd, J =9.4 Hz, 2.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 9.5 Hz, 1H),5.24 (s, 2H), 2.38 (s, 3H), 2.21 (s, 3H); ESI m/z 316 [M + H]+. 561-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.31-7.41 (m, 5H); 7.25 (dd, J = 2.7, 9.3Hz, 1H); 7.13 (d, J = 2.4 Hz, 1H); 6.76 (d, J = 9.3 Hz, 1H); 5.20 (s,2H); 2.29 (s, 3H); 2.15 (s, 3H); ESI MS m/z 281 [M + H]+. 57 1-benzyl-5-(5-methyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H); 7.34-7.39 (m, 6H); 7.23 (d, J= 2.4 Hz, 1H); 6.71 (d, J = 9.3 Hz, 1H); 5.19 (s, 2H); 2.40 (s, 3H); ESIMS m/z 267 [M + H]+. 58 1-benzyl-5- (isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H); 8.34 (s, 1H); 7.32-7.44 (m,7H); 6.72 (dd, J = 1.2, 9.0 Hz, 1H); 5.20 (s, 2H); ESI MS m/z 253 [M +H]+. 59 1-benzyl-5- (isothiazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H); 8.50 (s, 1H); 7.57 (dd, J =2.4, 9.3 Hz, 1H); 7.53 (d, J = 2.1 Hz, 1H); 7.33-7.40 (m, 5H); 6.76 (d,J = 9.3 Hz, 1H); 5.20 (s, 2H); ESI MS m/z 269 [M + H]+. 60 2-benzyl-6-((3,4- dimethoxy- phenyl) amino) pyridazin- 3(2H)-one

B 1H NMR (300 MHz, CDCl3) δ 7.41-7.44 (m, 2H); 7.28-7.36 (m, 4H);6.91-6.98 (m, 3H); 6.76- 6.82 (m, 2H); 5.24 (s, 2H); 3.87 (s, 3H); 3.77(s, 3H); ESI MS m/z 338 [M + H]+. 61 2-benzyl-6- ((3,5- dimethyl-isoxazol-4- yl)amino) pyridazin- 3(2H)-one

B 1H NMR (300 MHz, CDCl3) δ 7.29-7.39 (m, 5H); 6.98-7.01 (m, 1H);6.76-6.79 (m, 1H); 5.14 (s, 2H); 2.25 (s, 3H); 2.06 (s, 3H); ESI MS m/z297 [M + H]+. 62 1-benzyl-2′- hydroxy- [3,4′- bipyridin]- 6(1H)-one

F 1H NMR (300 MHz, CDCl3) δ 7.56-7.62 (m, 2H); 7.33-7.40 (m, 7H); 6.73(d, J = 9.3 Hz, 1H); 6.57 (s, 1H); 6.33 (d, J = 7.2 Hz, 1H); 5.21 (s,2H); ESI MS m/z 279 [M + H]+. 63 1-benzyl-5- (3,5- dimethyl- isoxazol-4-yl)-3- fluoro- pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.33-7.40 (m, 5H); 7.01 (dd, J = 2.1, 9.6Hz, 1H); 6.94 (d, J = 2.1 Hz, 1H); 5.23 (s, 2H); 2.29 (s, 3H); 2.15 (s,3H); ESI MS m/z 299 [M + H]+. 64 1-benzyl-3- chloro-5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 2.4 Hz, 1H); 7.35-7.38 (m, 5H);7.09 (d, J = 2.4 Hz, 1H); 5.23 (s, 2H); 2.29 (s, 3H); 2.15 (s, 3H); ESIMS m/z 315 [M + H]+. 65 1-benzyl-5- ((3,4- dimethoxy- phenyl) amino)pyridin- 2(1H)-one

B 1H NMR (300 MHz, DMSO-d6) δ 7.49 (d, J = 2.7 Hz, 1H); 7.24-7.38 (m,7H); 6.75 (d, J = 8.4 Hz, 1H); 6.45 (d, J = 9.6 Hz, 1H); 6.38 (d, J =2.4 Hz, 1H); 6.21 (dd, J = 2.4, 8.4 Hz, 1H); 5.09 (s, 2H); 3.64 (s, 3H);3.61 (s, 3H); ESI MS m/z 337 [M + H]+. 66 1-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-3- methyl- pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.32-7.37 (m, 5H); 7.09 (dd, J = 1.2, 2.4Hz, 1H); 7.02 (d, J = 2.1 Hz, 1H); 5.19 (s, 2H); 2.29 (s, 3H); 2.22 (s,3H); 2.16 (s, 3H); ESI MS m/z 295 [M + H]+. 67 1-benzyl-3- cyclopropyl-5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

I 1H NMR (300 MHz, CDCl3) δ 7.32-7.38 (m, 5H); 6.97 (d, J = 2.4 Hz, 1H);6.72 (d, J = 2.1 Hz, 1H); 5.20 (s, 2H); 2.28 (s, 3H); 2.15-2.25 (m, 1H);2.13 (s, 3H); 0.98-1.03 (m, 2H); 0.62-0.65 (m, 2H); ESI MS m/z 321 [M +H]+. 68 5-(3,5- dimethyl- isoxazol-4- yl)-1-(4- fluoro- benzoyl)pyridin- 2(1H)-one

H 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 2.4 Hz, 1H); 8.25-8.30 (m, 2H);7.76 (dd, J = 2.4, 8.4 Hz, 1H); 7.33 (d, J = 8.4 Hz, 1H); 7.19-7.24 (m,2H); 2.46 (s, 3H); 2.31 (s, 3H); ESI MS m/z 313 [M + H]+. 69 1-(4-chloro- benzoyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

H 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 2.4 Hz, 1H); 8.19 (d, J = 8.7Hz, 2H); 7.76 (dd, J = 2.4, 8.4 Hz, 1H); 7.52 (d, J = 8.7 Hz, 2H); 7.33(d, J = 7.8 Hz, 1H); 2.46 (s, 3H); 2.31 (s, 3H); ESI MS m/z [M + H]+. 701-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-(4- fluoro- phenyl)pyridin- 2(1H)-one

I 1H NMR (300 MHz, CDCl3) δ 7.67-7.72 (m, 2H); 7.36-7.40 (m, 5H); 7.34(d, J = 2.4 Hz, 1H); 7.18 (d, J = 2.7 Hz, 1H); 7.08-7.14 (m, 2H); 5.25(s, 2H); 2.34 (s, 3H); 2.20 (s, 3H); ESI MS m/z 375 [M + H]+. 71N-(1-benzyl- 5-(3,5- dimethyl- isoxazol-4- yl)-2-oxo- 1,2- dihydro-pyridin- 3-yl) acetamide

J 1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H); 8.24 (d, J = 2.4 Hz, 1H);7.68 (d, J = 2.4 Hz, 1H); 7.29-7.37 (m, 5H); 5.21 (s, 2H); 2.37 (s, 3H);2.20 (s, 3H); 2.12 (s, 3H); ESI MS m/z 338 [M + H]+. 72 1-benzyl-5-(3,5- dimethyl- isoxazol-4- yl)-3- (phenyl- amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H); 7.43-7.34 (m, 5H); 7.25-7.32 (m, 5H); 6.98 (d, J = 2.1 Hz, 1H); 6.90-6.96 (m, 1H); 5.22 (s, 2H);2.36 (s, 3H); 2.19 (s, 3H); ESI MS m/z 372 [M + H]+. 73 3-amino-1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.27-7.35 (m, 5H); 7.10 (d, J = 2.4 Hz,1H); 6.44 (d, J = 2.1 Hz, 1H); 5.28 (s, 2H); 5.13 (s, 2H); 2.34 (s, 3H);2.17 (s, 3H); ESI MS m/z 296 [M + H]+. 74 1-benzyl-3- (benzyl- amino)-5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.21-7.36 (m, 10H); 7.07 (d, J = 2.1 Hz,1H); 6.36 (t, J = 6.0 Hz, 1H); 5.97 (d, J = 2.1 Hz, 1H); 5.15 (s, 2H);4.32 (d, J = 6.0 Hz, 2H); 2.17 (s, 3H); 1.98 (s, 3H); ESI MS m/z 386[M + H]+. 75 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3- (methyl-amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, CDCl3) δ 7.29-7.36 (m, 6H); 6.55 (d, J = 2.1 Hz, 1H);6.16 (d, J = 1.8 Hz, 1H); 5.21 (s, 2H); 2.87 (s, 3H); 2.32 (s, 3H); 2.19(s, 3H); ESI MS m/z 310 [M + H]+. 76 6-(3,5- dimethyl- isoxazol-4-yl)-2-(4- (trifluoro- methoxy) benzyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 9.5Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 9.5 Hz, 1H), 5.34 (s,2H), 2.46 (s, 3H), 2.31 (s, 3H); ESI MS m/z 366 [M + H]+. 77 6-(3,5-dimethyl- isoxazol-4- yl)-2- (naphthalen- 2-ylmethyl) pyridazin-3(2H)-one

C 1H NMR (500 MHz, CDCl3) δ 7.91 (s, 1H), 7.82-7.80 (m, 3H), 7.57 (dd, J= 1.7, 8.5 Hz, 1H), 7.48-7.46 (m, 2H), 7.27 (s, 1H), 7.02 (d, J = 9.6Hz, 1H), 5.18 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H); ESI MS m/z 332 [M +H]+ 78 5-(3,5- dimethyl- isoxazol-4- yl)-1-(3- methoxy- benzyl) pyridin-2(1H)-one

D 1H NMR (500 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.16 (d, J = 2.4 Hz, 1H),6.89-6.87 (m, 3H), 6.83 (d, J = 9.4 Hz, 1H), 5.18 (s, 2H), 3.79 (s. 3H).2.29 (s, 3H), 2.15 (s, 3H); ESI MS m/z 311 [M + H]+ 79 5-(3,5- dimethyl-isoxazol-4- yl)-1- (thiophen-3- ylmethyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.39-7.32 (m, 3H), 7.20 (d, J = 2.1 Hz, 1H),7.08 (dd, J = 1.3, 4.9 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 5.22 (s, 2H),2.31 (s, 3H), 2.17 (s, 3H); ESI MS m/z 287 [M + H]+ 80 1-benzyl-5-(thiazol-5- yl)pyridin- 2(1H)-one

F 1H NMR (500 MHz, CDCl3) δ 8.69 (s, 1H), 7.82 (s, 1H), 7.53 (dd, J =2.1, 9.1 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.38-7.32 (m, 5H), 6.71 (d,J = 9.5 Hz, 1H), 5.12 (s, 2H); ESI MS m/z 269 [M + H]+ 81 1-benzyl-5-(5-methyl- 1H- imidazol-4- yl)pyridin- 2(1H)-one

F 1H NMR (500 MHz, CDCl3) δ 7.77-7.53 (m, 2H), 7.47 (s, 1H), 7.34- 7.30(m, 4H), 7.29-7.27 (m, 1H), 6.66 (d, J = 9.3 Hz, 1H), 5.19 (s, 2H) 2.92(s, 3H); ESI MS m/z 266 [M + H]+ 82 N-(4-((6- oxo-3- (3,4,5- trimethoxy-phenyl) pyridazin- 1(6H)- yl)methyl) phenyl) acetamide

C 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H),7.54 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.14 (s, 2H), 7.07(d, J = 9.9 Hz, 1H), 5.25 (s, 2H), 3.84 (s, 6H), 3.69 (s, 3H), 2.02 (s,3H); ESI-MS m/z 410 [M + H]+. 83 2-benzyl-6-(4- hydroxy-3- methoxy-phenyl) pyridazin- 3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.04 (d, J = 9.9 Hz, 1H),7.41-7.29 (m, 7H), 7.04 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H),5.30 (s, 2H), 3.82 (s, 3H); APCI- MS m/z 309 [M + H]+. 84 6-(3,5-dimethyl- isoxazol-4- yl)-2-(2- fluoro- benzyl)-4- methyl- pyridazin-3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 7.57 (d, J = 1.2 Hz, 1H), 7.39-7.33 (m,2H), 7.25-7.15 (m, 2H), 5.35 (s, 2H), 2.42 (s, 3H), 2.18 (s, 3H), 2.17(d, J = 1.2 Hz, 3H); APCI-MS m/z 314 [M + H]+. 85 2- (cyclo- propyl-methyl)-6- (3,5- dimethyl- isoxazol- 4-yl)-4- methyl- pyridazin-3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 7.55 (d, J = 1.2 Hz, 1H), 3.97 (d, J = 7.2Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 2.15 (d, J = 1.2 Hz, 3H), 1.30-1.23(m, 1H), 0.54-0.40 (m, 2H), 0.39-0.37 (m, 2H); APCI-MS m/z 260 [M + H]+.86 2-benzyl-6- (3,5- dimethyl- 1H-pyrazol- 4-yl) pyridazin- 3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 12.48 (br. s, 1H), 7.59 (d, J = 9.6 Hz,1H), 7.35-7.28 (m, 5H), 7.51 (d, J = 9.6 Hz, 1H), 5.26 (s, 2H), 2.25 (s,3H), 2.19 (s, 3H); ESI-MS m/z 281 [M + H]+. 87 6-(3,5- dimethyl-isoxazol-4- yl)-4- methyl-2- (pyridin-4- ylmethyl) pyridazin- 3(2H)-one

A 1H NMR (500 MHz, DMSO-d6) δ 8.53 (dd, J = 7.5, 3.0 Hz, 2H), 7.61 (d, J= 2.0 Hz, 1H), 7.28 (dd, J = 7.5, 3.0 Hz, 2H), 5.34 (s, 2H), 2.47 (s,3H), 2.25 (s, 3H), 2.17 (d, J = 2.0 Hz, 3H); ESI-MS m/z 297 [M + H]+. 882- (cyclobutyl- methyl)-6- (3,5- dimethyl- isoxazol-4- yl)pyridazin-3(2H)-one

C 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 9.5 Hz, 1H), 6.99 (d, J = 9.5Hz, 1H), 4.24 (d, J = 7.5 Hz, 2H), 2.94-2.88 (m, 1H), 2.53 (s, 3H), 2.38(s, 3H), 2.10-2.04 (m, 2H), 1.96-1.84 (m, 4H); ESI- MS m/z 260 [M + H]+.89 4-((3-(3,5- dimethyl- isoxazol-4- yl)-6- oxopyridazin- 1(6H)-yl)methyl)-N- methyl- benzamide

C 1H NMR (500 MHz, DMSO-d6) δ 8.39 (q, J = 4.5 Hz, 1H), 7.80 (d, J = 8.5Hz, 2H), 7.68 (d, J = 9.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.10 (d, J= 9.5 Hz, 1H), 5.34 (s, 2H), 2.76 (d, J = 4.5 Hz, 3H), 2.46 (s, 3H),2.25 (s, 3H); ESI-MS m/z 339 [M + H]+. 90 2-(2,6- difluoro- benzyl)-6-(3,5- dimethyl- isoxazol-4- yl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.9 Hz, 1H), 7.50-7.42 (m,1H), 7.17-7.12 (m, 2H), 7.08 (d, J = 9.6 Hz, 1H), 5.37 (s, 2H), 2.35 (s,3H), 2.07 (s, 3H); ESI-MS m/z 318 [M + H]+. 91 6-(3,5- dimethyl-isoxazol-4- yl)-2-(4- (trifluoro- methyl) benzyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 9.6Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 9.6 Hz, 1H), 5.40 (s,2H), 2.47 (s, 3H), 2.25 (s, 3H); ESI-MS m/z 350 [M + H]+ 92 6-(3,5-dimethyl- isoxazol-4- yl)-2- (2,4,6- trifluoro- benzyl) pyridazin-3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.6 Hz, 1H), 7.30-7.22 (m,2H), 7.08 (d, J = 9.9 Hz, 1H), 5.33 (s, 2H), 2.38 (s, 3H), 2.12 (s, 3H);ESI- MS m/z 336 [M + H]+. 93 6-(3,5- dimethyl- isoxazol-4- yl)-2-(2-fluorobenzyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, DMSO-d6) δ 7.67 (d, J = 9.5 Hz, 1H), 7.39-7.35 (m,2H), 7.24-7.17 (m, 2H), 7.09 (d, J = 10.0 Hz, 1H), 5.35 (s, 2H), 2.423H), 2.18 (s, 3H); ESI-MS m/z 300 [M + H]+. 94 6-(3,5- dimethyl-isoxazol-4- yl)-2-(2- (trifluoro- methyl) benzyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, DMSO-d6) δ 7.79 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 9.5Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.28 (d, J= 7.5 Hz, 1H), 7.15 (d, J = 9.5 Hz, 1H), 5.49 (s, 2H), 2.39 (s, 3H),2.11 (s, 3H); ESI-MS m/z 350 [M + H]+. 95 6-(3,5- dimethyl- isoxazol-4-yl)-2-(1-(2- fluorophenyl) ethyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, DMSO-d6) δ 7.65 (d, J = 9.5 Hz, 1H), 7.43 (td, J =7.5, 1.5 Hz, 1H), 7.37- 7.34 (m, 1H), 7.23-7.16 (m, 2H), 7.06 (d, J =9.5 Hz, 1H), 6.42 (q, J = 7.0 Hz, 1H), 2.49 (s, 3H), 2.14 (s, 3H), 1.70(d, J = 7.0 Hz, 3H); ESI-MS m/z 314 [M + H]+. 96 2-(2-chloro- 6-fluoro-benzyl)- 6-(3,5- dimethyl- isoxazol-4- yl)pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.6 Hz, 1H), 7.48-7.38 (m,2H), 7.33-7.27 (m, 1H), 7.10 (d, J = 9.6 Hz, 1H), 5.43 (s, 2H), 2.29 (s,3H), 1.97 (s, 3H); ESI-MS m/z 334 [M + H]+. 97 6-(3,5- dimethyl-isoxazol-4- yl)-2- (isoxazol-4- ylmethyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.63 (s, 1H), 7.67 (d, J =9.9 Hz, 1H), 7.09 (d, J = 9.6 Hz, 1H), 5.20 (s, 2H), 2.50 (s, 3H), 2.23(s, 3H); ESI-MS m/z 273 [M + H]+. 98 5-(5- amino-3- methyl- isoxazol-4-yl)-1- benzyl- pyridin- 2(1H)-one

F 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J = 2.4 Hz, 1H), 7.41-7.27 (m,6H), 6.68 (br. s, 2H), 6.45 (d, J = 9.3 Hz, 1H), 5.11 (s, 2H), 2.01 (s,3H); ESI-MS m/z 282 [M + H]+. 99 2-benzyl-6- ((5,6- dimethoxy-pyridin-2- yl)amino) pyridazin- 3(2H)-one

B 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.52 (d, J = 9.9 Hz, 1H),7.36-7.25 (m, 7H), 6.93 (d, J = 9.9 Hz, 1H), 5.15 (s, 2H), 3.84 (s, 3H),3.72 (s, 3H); ESI-MS m/z 339 [M + H]+. 100 2-benzyl-6- (3,4- dimethoxy-phenoxy) pyridazin- 3(2H)-one

No general proce- dure 1H NMR (300 MHz, DMSO-d6) δ 7.38 (d, J = 9.6 Hz,1H), 7.32-7.20 (m, 5H), 7.09 (d, J = 9.6 Hz, 1H), 6.93 (d, J = 8.7 Hz,1H), 6.83 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.7, 2.7 Hz, 1H), 5.03 (s,2H), 3.74 (s, 3H), 3.66 (s, 3H); ESI-MS m/z 339 [M + H]+. 101 5-(3,5-dimethyl- isoxazol-4- yl)-1-(1-(4- fluorophenyl) ethyl) pyridin-2(1H)-one

E 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 2.1 Hz, 1H), 7.48-7.41 (m,3H), 7.23-7.17 (m, 2H), 6.51 (d, J = 9.3 Hz, 1H), 6.20 (q, J = 7.2 Hz,1H), 2.27 (s, 3H), 2.11 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H); ESI-MS m/z313 [M + H]+. 102 6-(3,5- dimethyl- isoxazol-4- yl)-2- (quinolin-8-ylmethyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.43 (dd,J = 8.4, 1.8 Hz, 1H), 7.96 (dd, J = 8.1, 1.2 Hz, 1H), 7.71 (d, J = 9.6Hz, 1H), 7.63-7.55 (m, 2H), 7.43 (dd, J = 6.9, 1.2 Hz, 1H), 7.15 (d, J =9.9 Hz, 1H), 5.94 (s, 2H), 2.33 (s, 3H), 2.03 (s, 3H); ESI-MS m/z 333[M + H]+. 103 1-(1-(2- chloro- phenyl) ethyl)-5- (3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.57-7.36 (m, 5H), 7.34 (d, J = 2.1 Hz,1H), 6.50 (d, J = 9.3 Hz, 1H), 6.22 (q, J = 6.9 Hz, 1H), 2.20 (s, 3H),2.02 (s, 3H), 1.70 (d, J = 6.9 Hz, 3H); ESI-MS m/z 329 [M + H]+. 1045-(3,5- dimethyl- isoxazol-4- yl)-1-(1-(3- fluorophenyl) ethyl) pyridin-2(1H)-one

E 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J = 2.4 Hz, 1H), 7.47 (dd, J =9.3, 2.4 Hz, 1H), 7.40 (dd, J = 7.8, 6.0 Hz, 1H), 7.26-7.12 (m, 3H),6.52 (d, J = 9.3 Hz, 1H), 6.20 (q, J = 7.2 Hz, 1H), 2.29 (s, 3H), 2.12(s, 3H), 1.75 (d, J = 7.2 Hz, 3H); ESI-MS m/z 313 [M + H]+. 105 1-(1-(4-chlorophenyl) ethyl)-5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.67 (d, J = 2.1Hz, 1H), 7.47 (dd, J =9.3, 2.4 Hz, 1H), 7.43- 7.37 (m, 4H), 6.51 (d, J = 9.3 Hz, 1H), 6.18 (q,J = 7.2 Hz, 1H), 2.29 (s, 3H), 2.12 (s, 3H), 1.74 (d, J = 7.2 Hz, 3H);ESI-MS m/z 329 [M + H]+. 106 5-(3,5- dimethyl- isoxazol-4- yl)-1-(2-phenyl- propan- 2-yl) pyridin- 2(1H)-one

E 1H NMR (300 MHz, DMSO-d6) δ 7.85 (d, J = 2.1 Hz, 1H), 7.49 (dd, J =9.3, 2.4 Hz, 1H), 7.31- 7.26 (m, 2H), 7.20-7.13 (m, 3H), 6.31 (d, J =9.3 Hz, 1H), 2.42 (s, 3H), 2.24 (s, 3H), 1.87 (s, 6H); ESI- MS m/z 309[M + H]+. 107 6-(3,5- dimethyl- isoxazol-4- yl)-2- (thiophen-3-ylmethyl) pyridazin- 3(2H)-one

C 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J = 9.6 Hz, 1H), 7.51 (dd, J =4.8, 3.0 Hz, 1H), 7.47 (dd, J = 3.0, 1.5 Hz, 1H), 7.10 (dd, J = 4.8, 1.2Hz, 1H), 7.08 (d, J = 9.6 Hz, 1H), 5.28 (s, 2H), 2.48 (s, 3H), 2.27 (s,3H); ESI-MS m/z 288 [M + H]+. 108 (R)-6-(3,5- dimethyl- isoxazol-4-yl)-2-(1- phenyl- ethyl) pyridazin- 3(2H)-one

K 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.6 Hz, 1H), 7.35-7.27 (m,5H), 7.06 (d, J = 9.6 Hz, 1H), 6.27 (q, J = 7.2 Hz, 1H), 2.46 (s, 3H),2.24 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ESI-MS m/z 296 [M + H]+;Chiralcel OD (10% EtOH in heptane, 0.8 mL/min): tR = 22.95 min. 109(S)-6-(3,5- dimethyl- isoxazol-4- yl)-2-(1- phenyl- ethyl) pyridazin-3(2H)-one

K 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 9.6 Hz, 1H), 7.35-7.27 (m,5H), 7.06 (d, J = 9.6 Hz, 1H), 6.27 (q, J = 7.2 Hz, 1H), 2.46 (s, 3H),2.24 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); ESI-MS m/z 296 [M + H]+;Chiralcel OD (10% EtOH in heptane, 0.8 mL/min): tR = 24.82 min. 110(S)-5-(3,5- dimethyl- isoxazol-4- yl)-1-(1-(4- fluoro- phenyl) ethyl)pyridin- 2(1H)-one

K 1H NMR (300 MHz, DMSO-d6) 7.65 (d, J = 2.1 Hz, 1H), 7.48-7.41 (m, 3H),7.23-7.17 (m, 2H), 6.51 (d, J = 9.3 Hz, 1H), 6.20 (q, J = 7.2 Hz, 1H),2.27 (s, 3H), 2.11 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H); ESI-MS m/z 313[M + H]+; Chiralcel OD (10% EtOH in heptane, 0.8 mL/min): tR = 11.07min. 111 (R)-5-(3,5- dimethyl- isoxazol-4- yl)-1-(1-(4- fluorophenyl)ethyl) pyridin- 2(1H)-one

K 1H NMR (300 MHz, DMSO-d6) δ 7.65 (d, J = 2.1 Hz, 1H), 7.48-7.41 (m,3H), 7.23-7.17 (m, 2H), 6.51 (d, J = 9.3 Hz, 1H), 6.20 (q, J = 7.2 Hz,1H), 2.27 (s, 3H), 2.11 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H); ESI-MS m/z313 [M + H]+; Chiralcel OD (10% EtOH in heptane, 0.8 mL/min): tR = 18.19min. 112 5-(3,5- dimethyl- isoxazol-4- yl)-1-(1- (pyridin-2- yl)ethyl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 8.56 (dd, J = 3.9, 0.9 Hz, 1H), 7.82 (td,J = 7.5, 1.8 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 9.3, 2.7Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.35-7.31 (m, 1H), 6.49 (d, J = 9.0Hz, 1H), 6.23 (q, J = 7.2 Hz, 1H), 2.33 (s, 3H), 2.16 (s, 3H), 1.74 (d,J = 7.2 Hz, 3H); ESI-MS m/z 296 [M + H]+. 113 1-(1-(3- chloro- phenyl)ethyl)-5- (3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

E 1H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J = 2.4 Hz, 1H), 7.50-7.30 (m,5H), 6.52 (d, J = 9.3 Hz, 1H), 6.18 (q, J = 7.2 Hz, 1H), 2.30 (s, 3H),2.13 (s, 3H), 1.75 (d, J = 7.2 Hz, 3H); ESI-MS m/z 329 [M + H]+. 1141-benzyl-6- chloro-5- (3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J = 8.4 Hz, 1H), 7.52-7.49 (m,2H), 7.44-7.39 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 5.36 (s, 2H), 2.28 (s,3H), 2.10 (s, 3H); ESI-MS m/z 315 [M + H]+. 115 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-6- methyl- pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.54 (d, J = 8.4 Hz, 1H), 7.51-7.48 (m,2H), 7.43-7.34 (m, 3H), 6.78 (d, J = 8.4 Hz, 1H), 5.36 (s, 2H), 2.23 (s,3H), 2.22 (s, 3H), 2.04 (s, 3H); ESI-MS m/z 295 [M + H]+. 116 2-(4-(methyl- sulfonyl) benzyl)-6- (3,4,5- trimethoxy- phenyl) pyridazin-3(2H)-one

C 1H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 10.0Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.0 (d, J = 9.5 Hz, 1H), 6.96 (s,2H), 5.48 (s, 2H), 3.96 (s, 6H), 3.90 (s, 3H), 3.02 (s, 3H). ESI MS m/z431 [M + H]+. 117 2-(4- methoxy- benzyl)-6- (3,4,5- trimethoxy- phenyl)pyridazin- 3(2H)-one

No general proce- dure 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 9.5 Hz,1H), 7.44 (d, J = 8.5 Hz, 2H), 7.0 (d, J = 9.5 Hz, 1H), 6.96 (s, 2H),6.86 (d, J = 8.5 Hz, 2H), 5.34 (s, 2H), 3.92 (s, 6H), 3.89 (s, 3H), 3.78(s, 3H). ESI MS m/z 383 [M + H]+. 118 2-((6-oxo- 3-(3,4,5- trimethoxy-phenyl) pyridazin- 1(6H)- yl)methyl) benzonitrile

C 1H NMR (500 MHz, CDCl3): δ 7.70-7.66 (m, 2H), 7.58-7.55 (m, 1H),7.43-7.39 (m, 1H), 7.08 (s, 2H), 7.04 (d, J = 9.5 Hz, 2H), 5.65 (s, 2H),3.93 (s, 6H), 3.89 (s, 3H). ESI MS m/z 378 [M + H]+. 119 2-(3- methoxy-benzyl)-6- (3,4,5- trimethoxy- phenyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, CDCl3): δ 7.62 (d, J = 9.5 Hz, 1H), 7.26-7.23 (m,1H), 7.05-7.04 (m, 1H), 7.03-7.00 (m, 2H), 6.97 (s, 2H), 6.83-6.82 (m,1H), 5.37 (s, 2H), 3.92 (s, 6H), 3.89 (s, 3H), 3.79 (s, 3H). ESI MS m/z383 [M + H]+. 120 2-(4-(tert- butyl)benzyl)- 6-(3,4,5- trimethoxy-phenyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 9.5 Hz, 1H), 7.41 (d, J = 8.5Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.0 (d, J = 9.5 Hz, 1H), 6.98 (s,2H), 5.38 (s, 2H), 3.92 (s, 6H), 3.89 (s, 3H), 1.29 (s, 9H). ESI MS m/z409 [M + H]+. 121 5-(3,5- dimethyl- isoxazol-4- yl)-1-(2- methyl-benzyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, CDCl3): δ 7.28-7.21 (m, 2H), 7.15-7.14 (m, 2H),7.11-7.11 (m, 2H), 6.69 (d, J = 9.5 Hz, 1H), 5.14 (s, 2H), 2.34 (s, 3H),2.28 (s, 3H), 2.15 (s, 3H). ESI MS m/z 295 [M + H]+. 122 5-(3,5-dimethyl- isoxazol-4- yl)-1-(3- methyl- benzyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, CDCl3): δ 7.29-7.21 (m, 4H), 7.13-7.11 (m, 1H), 6.90(d, J = 2.5 Hz, 1H), 6.71 (d, J = 9.5 Hz, 1H), 5.18 (s, 2H), 2.28 (s,3H), 2.22 (s, 3H), 2.09 (s, 3H). ESI MS m/z 295 [M + H]+. 123 5-(3,5-dimethyl- isoxazol-4- yl)-1-(2- (trifluoro- methyl) benzyl) pyridin-2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.84 (d, J = 2.5 Hz, 1H), 7.80 (d, J =7.7 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.61 (dd, J = 2.6, 9.4 Hz, 1H),7.51 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.58 (d, J = 9.4 Hz,1H), 5.35 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H). ESI MS m/z 349 [M + H]+.124 5-(3,5- dimethyl- isoxazol-4- yl)-1-(1-(2- fluoro- phenyl) ethyl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.60-7.35 (m, 4H), 7.30-7.15 (m, 2H),6.49 (d, J = 9.4 Hz, 1H), 6.28 (q, J = 7.0 Hz, 1H), 2.24 (s, 3H), 2.06(s, 3H), 1.71 (d, J = 7.0 Hz, 3H). ESI MS m/z 313 [M + H]+. 125 5-(3,5-dimethyl- isoxazol-4- yl)-1-(1- phenylethyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.60 (d, J = 2.4 Hz, 1H), 7.45 (dd, J =2.5, 9.4 Hz, 1H), 7.40- 7.35 (m, 4H), 7.34-7.27 (m, 1H), 6.51 (d, J =9.4 Hz, 1H), 6.22 (q, J = 7.0 Hz, 1H), 2.25 (s, 3H), 2.09 (s, 3H), 1.74(d, J = 7.0 Hz, 3H). ESI MS m/z 295 [M + H]+. 126 1-(3- chlorobenzyl)-5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.66-7.28 (m, 5H), 6.52 (d,J = 9.4 Hz, 1H), 5.13 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z315 [M + H]+. 127 1-(2- chlorobenzyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.81 (d, J = 2.5 Hz, 1H), 7.57 (dd, J =2.5, 9.4 Hz, 1H), 7.54- 7.49 (m, 1H), 7.37-7.30 (m, 2H), 6.99-6.93 (m,1H), 6.56 (d, J = 9.4 Hz, 1H), 5.21 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H).ESI MS m/z 315 [M + H]+. 128 1-(4- chlorobenzyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.94 (d, J = 2.5 Hz, 1H), 7.50 (dd, J =2.5, 9.4 Hz, 1H), 7.41 (q, J = 10.1 Hz, 4H), 6.51 (d, J = 9.4 Hz, 1H),5.12 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 315 [M + H]+. 1295-(3,5- dimethyl- isoxazol-4- yl)-1- (pyridin-4- ylmethyl) pyridin-2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.93 (s, 2H), 7.55 (d, J =9.4 Hz, 1H), 7.24 (s, 2H), 6.54 (d, J = 9.4 Hz, 1H), 5.17 (s, 2H), 2.37(s, 3H), 2.20 (s, 3H). ESI MS m/z 282 [M + H]+. 130 5-(3,5- dimethyl-isoxazol-4- yl)-1-(4- methoxy- benzyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.90 (s, 1H), 7.46 (d, J = 9.4 Hz, 1H),7.34 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.48 (d, J = 9.4 Hz,1H), 5.04 (s, 2H), 3.72 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H). ESI MS m/z311 [M + H]+. 131 1-(3,4- dimethoxy- benzyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.90 (s, 1H), 7.46 (d, J = 9.4 Hz, 1H),7.08 (s, 1H), 6.91 (s, 2H), 6.49 (d, J = 9.4 Hz, 1H), 5.04 (s, 2H), 3.72(s, 6H), 2.34 (s, 3H), 2.18 (s, 3H). ESI MS m/z 341 [M + H]+. 1325-(3,5- dimethyl- isoxazol-4- yl)-2-(4- fluorobenzyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.94 (d, J = 2.5 Hz, 1H), 7.49 (dd, J =2.5, 9.4 Hz, 1H), 7.46- 7.40 (m, 2H), 7.22-7.15 (m, 2H), 6.50 (d, J =9.4 Hz, 1H), 5.11 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H). ESI MS m/z 299[M + H]+. 133 (S)-5-(3,5- dimethyl- isoxazol-4- yl)-1-(1- phenylethyl)pyridin- 2(1H)-one

K 1H NMR (500 MHz, DMSO-d6): δ 7.60 (d, J = 2.4 Hz, 1H), 7.45 (dd, J =2.5, 9.4 Hz, 1H), 7.40- 7.35 (m, 4H), 7.34-7.27 (m, 1H), 6.51 (d, J =9.4 Hz, 1H), 6.22 (q, J = 7.0 Hz, 1H), 2.26 (s, 3H), 2.09 (s, 3H), 1.74(d, J = 7.0 Hz, 3H). ESI MS m/z 295 [M + H]+. 134 (R)-5-(3,5- dimethyl-isoxazol-4- yl)-1-(1- phenylethyl) pyridin- 2(1H)-one

K 1H NMR (500 MHz, DMSO-d6): δ 7.60 (d, J = 2.4 Hz, 1H), 7.45 (dd, J =2.5, 9.4 Hz, 1H), 7.40- 7.35 (m, 4H), 7.34-7.27 (m, 1H), 6.51 (d, J =9.4 Hz, 1H), 6.22 (q, J = 7.0 Hz, 1H), 2.26 (s, 3H), 2.09 (s, 3H), 1.74(d, J = 7.0 Hz, 3H). ESI MS m/z 295 [M + H]+. 135 2-((5-(3,5- dimethyl-isoxazol-4- yl)-2- oxopyridin- 1(2H)- yl)methyl) benzonitrile

D 1H NMR (500 MHz, DMSO-d6): δ 7.92 (d, J = 2.5 Hz, 1H), 7.88 (dd, J =1.0, 7.7 Hz, 1H), 7.68 (td, J = 1.2, 7. Hz, 1H), 7.58 (dd, J = 2.5, 9.4Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.54 (d, J= 9-4 Hz, 1H), 5.33 (s, 2H), 2.39 (s, 3H), 2.22 (s, 3H). ESI MS m/z 306[M + H]+. 136 1-(2,4- dichloro- benzyl)-5- (3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.83 (d, J = 2.5 Hz, 1H), 7.69 (d, J =2.2 Hz, 1H), 7.57 (dd, J = 2.5, 9.4 Hz, 1H), 7.42 (dd, J = 2.2, 9.4 Hz,1H), 7.00 (d, J = 9.4 Hz, 1H), 6.56 (d, J = 9.4 Hz, 1H), 5.18 (s, 2H),2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 349 [M + H]+. 137 4-((5-(3,5-dimethyl- isoxazol-4- yl)-2- oxopyridin- 1(2H)- yl)methyl) benzonitrile

D 1H NMR (500 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.83 (d, J = 9.4 Hz, 2H),7.53 (dd, J = 2.5, 9.4 Hz, 1H), 7.50 (d, J = 9.4 Hz, 2H), 6.53 (d, J =9.4 Hz, 1H), 5.22 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H). ESI MS m/z 306[M + H]+. 138 1-(2,4- difluoro- benzyl)-5- (3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.86 (d, J = 2.5 Hz, 1H), 7.52 (dd, J =2.5, 9.4 Hz, 1H), 7.36- 7.24 (m, 2H), 7.11-7.05 (m, 1H), 6.50 (d, J =9.4 Hz, 1H), 5.14 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 317[M + H]+. 139 1-(4-chloro-2- fluorobenzyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.88 (d, J = 2.5 Hz, 1H), 7.53 (dd, J =2.5, 9.4 Hz, 1H), 7.47 (dd, J = 2.1, 10.1 Hz, 1H), 7.32-7.22 (m, 2H),6.51 (d, J = 9.4 Hz, 1H), 5.15 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H). ESIMS m/z 333 [M + H]+. 140 1-(2-chloro-4- fluorobenzyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.81 (d, J = 2.4 Hz, 1H), 7.57 (dd, J =2.7, 9.4 Hz, 1H), 7.52 (dd, J = 2.7, 8.7 Hz, 1H), 7.22 (td, J = 2.7, 8.6Hz, 1H), 7.08 (dd, J = 6.1, 8.7 Hz, 1H), 6.55 (d, J = 9.3 Hz, 1H), 5.17(s, 2H), 2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z 333 [M + H]+. 1411-(4-chloro-3- fluorobenzyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin-2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.95 (d, J = 2.5 Hz, 1H), 7.58 (t, J =8.1 Hz, 1H), 7.52 (dd, J = 2.6, 9.3 Hz, 1H), 7.43 (dd, J = 1.9, 10.3 Hz,1H), 7.22 (dd, J = 1.5, 8.3 Hz, 1H), 6.52 (d, J = 9.4 Hz, 1H), 5.13 (s,2H), 2.37 (s, 3H), 2.20 (s, 3H). ESI MS m/z 333 [M + H]+. 142 5-(3,5-dimethyl- isoxazol-4- yl)-1- (3,4,5- trifluoro- benzyl) pyridin-2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.94 (d, J = 2.5 Hz, 1H), 7.52 (dd, J =2.5, 9.4 Hz, 1H), 7.38- 7.30 (m, 2H), 6.52 (d, J = 9.4 Hz, 1H), 5.10 (s,2H), 2.37 (s, 3H), 2.20 (s, 3H). ESI MS m/z 335 [M + H]+. 143 2-((1H-benzo[d] imidazol-5- yl)methyl)- 6-(3,5- dimethyl- isoxazol-4-yl)pyridazin- 3(2H)-one

L 1H NMR (500 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.65 (d, J = 9.6 Hz, 1H),7.60 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 1.4, 8.3 Hz, 1H),7.07 (d, J = 9.7 Hz, 1H), 5.39 (s, 2H), 2.47 (s, 3H), 2.27 (s, 3H). ESIMS m/z 322 [M + H]+. 144 6-(3,5- dimethyl- isoxazol-4- yl)-2- (3,4,5-trifluoro- benzyl) pyridazin- 3(2H)-one

C 1H NMR (500 MHz, DMSO-d6): δ 7.68 (d, J = 9.6 Hz, 1H), 7.35-7.27 (m,2H), 7.10 (d, J = 9.7 Hz, 1H), 5.29 (s, 2H), 2.48 (s, 3H), 2.27 (s, 3H).ESI MS m/z 336 [M + H]+. 145 5-(3,5- dimethyl- isoxazol-4- yl)-1-(4-(methyl- sulfonyl) benzyl) pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.98 (d, J = 2.4 Hz, 1H), 7.91 (d, J =8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.54 (dd, J = 2.6, 9.4 Hz, 1H),6.53 (d, J = 9.5 Hz, 1H), 5.24 (s, 2H), 3.19 (s, 3H), 2.37 (s, 3H), 2.21(s, 3H). ESI MS m/z 359 [M + H]+. 146 1-((1H- benzo[d] imidazol-5-yl)methyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

L 1H NMR (500 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H),7.62 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 2.6, 9.3 Hz, 1H),7.27 (dd, J = 1.6, 8.3 Hz, 1H), 6.54 (d, J = 9.3 Hz, 1H), 5.23 (s, 2H),2.34 (s, 3H), 2.17 (s, 3H). ESI MS m/z 321 [M + H]+. 147 1-(3-chloro-4-fluorobenzyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.97 (d, J = 2.4 Hz, 1H), 7.65 (d, J =7.7 Hz, 1H), 7.51 (dd, J = 2.4, 9.3 Hz, 1H), 7.44- 7.38 (m, 2H), 6.51(d, J = 9.4 Hz, 1H), 5.10 (s, 2H), 2.36 (s, 3H), 2.20 (s, 3H). ESI MSm/z 333 [M + H]+. 148 1-((1H- indazol- 5-yl) methyl)-5- (3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

L 1H NMR (500 MHz, DMSO-d6): δ 13.06 (s, 1H), 8.06 (s, 1H), 7.95 (d, J =2.4 Hz, 1H), 7.78 (s, 1H), 7.55-7.40 (m, 3H), 6.51 (d, J = 9.3 Hz, 1H),5.22 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H). ESI MS m/z 321 [M + H]+. 1491-((1H- indol-4- yl)methyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin-2(1H)-one

L 1H NMR (500 MHz, DMSO-d6): δ 11.21 (s, 1H), 7.72 (d, J = 2.5 Hz, 1H),7.48 (dd, J = 2.5, 9.3 Hz, 1H), 7.39-7.33 (m, 2H), 7.05 (t, J = 7.4 Hz,1H), 6.87 (d, J = 7.0 Hz, 1H), 6.63-6.58 (m, 1H), 6.53 (d, J = 9.4 Hz,1H), 5.40 (s, 2H), 2.25 (s, 3H), 2.09 (s, 3H). ESI MS m/z 320 [M + H]+.150 1-((4- chloro- phenyl) sulfonyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

H 1H NMR (300 MHz, CDCl3) δ 8.16 (dd, J = 2.4, 0.6 Hz, 1H), 8.02 (dt, J= 6.9, 2.4 Hz, 2H), 7.69 (dd, J = 8.4, 2.7 Hz, 1H), 7.57 (dt, J = 6.6,2.4 Hz, 2H), 7.21 (dd, J = 8.4, 0.6 Hz, 1H), 2.41 (s, 3H), 2.26 (s, 3H);ESI-MS m/z 365 [M + H]+. 151 5-(3-amino-5- methyl- isoxazol- 4-yl)-1-benzyl- pyridin- 2(1H)-one

no general proce- dure 1H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J = 2.1 Hz,1H), 7.42 (dd, J = 2.7, 9.3 Hz, 1H), 7.28- 7.36 (m, 5H), 5.49 (d, J =9.3 Hz, 1H), 5.43 (s, 2H), 5.13 (s, 2H), 2.21 (s, 3H). ESI MS m/z 282[M + H]+. 152 3-amino-1-(4- chlorobenzyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.42 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 9.0Hz, 2H), 7.13 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 5.29 (s,2H), 5.12 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); ESI MS m/z 330 [M + H]+.153 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-(4- methyl-piperazin-1- yl)pyridin- 2(1H)-one, hydrochloride

J 1H NMR (500 MHz, DMSO-d6) δ 10.65 (br s, 1H), 7.64 (d, J = 2.2 Hz,1H), 7.36-7.33 (m, 4H), 7.31-7.26 (m, 1H), 6.81 (d, J = 2.2 Hz, 1H),5.16 (s, 2H), 3.88 (d, J = 13.0 Hz, 2H), 3.45 (d, J = 11.7 Hz, 2H),3.17-3.11 (m, 2H), 2.92 (t, J = 12.0 Hz, 2H), 2.80 (s, 3H), 2.37 (s,3H), 2.20 (s, 3H); ESI m/z 379 [M + H]+. 154 1-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-4- methoxy- pyridin- 2(1H)-one

G 1H NMR (500 MHz, CDCl3) δ 7.36-7.29 (m, 5H), 6.95 (s, 1H), 6.04 (s,1H), 5.13 (s, 2H), 3.77 (s, 3H), 2.19 (s, 3H), 2.07 (s, 3H); ESI m/z 311[M + H]+. 155 1-(3,4- dichloro- benzyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

D 1H NMR (500 MHz, DMSO-d6): δ 7.97 (d, J = 2.4 Hz, 1H), 7.67 (d, J =2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 2.6, 9.4 Hz, 1H),7.35 (dd, J = 2.2, 8.4 Hz, 1H), 6.51 (d, J = 9.4 Hz, 1H), 5.12 (s, 2H),2.37 (s, 3H), 2.20 (s, 3H). ESI MS m/z 349 [M + H]+. 156 1-benzyl-5-(3,5- dimethyl- isoxazol-4- yl)-3-((4- fluorophenyl) amino) pyridin-2(1H)-one

J 1H NMR (500 MHz, CDCl3) δ 7.35-7.33 (m, 5H), 7.15-7.12 (m, 2H),7.05-7.02 (m, 3H), 6.68 (d, J = 2.1 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H),5.25 (s, 2H) 2.28 (s, 3H), 2.15 (s, 3H); ESI MS m/z 390 [M + H]+. 1571-benzyl- 5-(3,5- dimethyl- isoxazol-4- yl)-3-((3- fluorophenyl) amino)pyridin- 2(1H)-one

J 1H NMR (500 MHz, CDCl3) δ 7.40-7.26 (m, 6H), 6.92-6.87 (m, 3H),6.73-6.67 (m, 2H), 5.25 (s, 2H) 2.31 (s, 3H), 2.18 (s, 3H). ESI MS m/z390 [M + H]+. 158 1-benzyl-5-(3- (hydroxy- methyl)-5- methyl-isoxazol-4- yl)pyridin- 2(1H)-one

F 1H NMR (500 MHz, DMSO-d6): δ 7.96 (d, J = 2.4 Hz, 1H), 7.59 (dd, J =2.6, 9.4 Hz, 1H), 7.39- 7.33 (m, 4H), 7.32-7.25 (m, 1H), 6.50 (d, J =9.4 Hz, 1H), 5.47 (t, J = 5.6 Hz, 1H), 5.13 (s, 2H), 4.46 (d, J = 5.6Hz, 1H), 2.39 (s, 3H). ESI MS m/z 297 [M + H]+. 159 1-(4- chlorobenzyl)-5-(3- (hydroxy- methyl)-5- methyl- isoxazol- 4-yl)pyridin- 2(1H)-one

F 1H NMR (500 MHz, DMSO-d6): δ 7.97 (d, J = 2.4 Hz, 1H), 7.60 (dd, J =2.6, 9.4 Hz, 1H), 7.45- 7.35 (m, 4H), 6.50 (d, J = 9.4 Hz, 1H), 5.46 (t,J = 5.5 Hz, 1H), 5.11 (s, 2H), 4.47 (d, J = 5.6 Hz, 1H), 2.39 (s, 3H).ESI MS m/z 331 [M + H]+. 160 1-benzyl-5-(3- methyliso- thiazol-4-yl)pyridin- 2(1H)-one

F 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H),7.37 (dd, J = 9.3, 2.7 Hz, 1H), 7.37-7.25 (m, 5H), 6.51 (d, J = 9.3 Hz,1H), 5.14 (s, 2H), 2.44 (s, 3H); ESI MS m/z 283 [M + H]+. 1611-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3- (piperazin-1- yl)pyridin-2(1H)-one, hydrochloride

M 1H NMR (500 MHz, DMSO-d6) δ 8.96 (br s, 2H), 7.65 (d, J = 2.2 Hz, 1H),7.35-7.28 (m, 5H), 6.80 (d, J = 2.2 Hz, 1H), 5.15 (s, 2H), 3.37-3.28 (m,4H), 3.24-3.14 (m, 4H), 2.37 (s, 3H), 2.20 (s, 3H); ESI m/z 365 [M +H]+. 162 5-(3,5- dimethyl- isoxazol-4- yl)-1-(2- methoxy- benzyl)pyridin- 2(1H)-one

G 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J = 2.4 Hz, 1H), 7.51 (dd, J =9.4 Hz, 2.6 Hz, 1H), 7.34- 7.25 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H),7.01-6.87 (m, 2H), 6.51 (d, J = 9.3 Hz, 1H), 5.07 (s, 2H), 3.84 (s, 3H),2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 311 [M + H]+. 163 5-(3,5- dimethyl-isoxazol-4- yl)-1- (pyrimidin- 2-ylmethyl) pyridin- 2(1H)-one

G 1H NMR (300 MHz, DMSO-d6) δ 8.77 (d, J = 4.8 Hz, 2H), 7.90 (d, J = 2.1Hz, 1H), 7.56 (dd, J = 9.4 Hz, 2.6 Hz, 1H), 7.43 (q, J = 4.8 Hz, 1H),6.50 (d, J = 9.6 Hz, 1H), 5.35 (s, 2H), 2.39 (s, 3H), 2.22 (s, 3H); ESIm/z 283 [M + H]+. 164 2-benzyl-4-(2- hydroxy-3,4- dimethoxy- phenyl)phthalazin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 7.4 Hz,1H), 7.76-7.66 (m, 2H), 7.49 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 7.8 Hz,1H), 7.34-7.28 (m, 2H), 7.27-7.22 (m, 1H), 7.04 (d, J = 8.6 Hz, 1H),6.80 (d, J = 8.6 Hz, 1H), 5.47 (s, 2H), 3.94 (s, 6H), 3.64 (s, 3H). 1652-benzyl-4-(4- hydroxy-3- methoxy- phenyl) phthalazin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.54-8.52 (m, 1H),7.79-7.71 (m, 3H), 7.52 (d, J = 7.2 Hz, 2H), 7.34-7.25 (m, 4H), 7.11-7.04 (m, 2H), 5.82 (s, 1H), 5.47 (s, 2H), 3.93 (s, 3H); ESI MS m/z 359[M + 1]+. 166 2-benzyl-4- (3,4- dimethoxy- phenyl) isoquinolin-1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 7.81 Hz,1H), 7.47- 7.66 (m, 3H), 7.24- 7.42 (m, 5H), 7.06 (s, 1H), 6.85-6.98 (m,3H), 5.27 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H). ESI MS m/z 372 [M + H]+.167 2-benzyl-4- (3,5- dimethyl- isoxazol-4- yl) isoquinolin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.8 Hz,1H), 7.60-7.68 (m, 1H), 7.51-7.60 (m, 1H), 7.29-7.39 (m, 5H), 7.19 (d, J= 7.8 Hz, 1H), 6.97 (s, 1H), 5.18-5.33 (m, 2H), 2.23 (s, 3H), 2.06 (s,3H); ESI MS m/z 331 [M + H]+. 168 2-benzyl-4- (3,4,5- trimethoxy-phenyl) isoquinolin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 7.8 Hz,1H), 7.49-7.66 (m, 3H), 7.28-7.41 (m, 5H), 7.08 (s, 1H), 6.57 (s, 2H),5.28 (s, 2H), 3.91 (s, 3H), 3.85 (s, 6H); ESI MS m/z 402 [M + H]+. 1692-benzyl-4-(4- hydroxy-3- methoxy- phenyl) isoquinolin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.2 Hz,1H), 7.58-7.65 (m, 1H), 7.50-7.57 (m, 2H), 7.28-7.40 (m, 5H), 7.05 (s,1H), 6.99 (d, J = 8.6 Hz, 1H), 6.84-6.89 (m, 2H), 5.70 (s, 1H), 5.27 (s,2H), 3.89 (s, 3H); ESI MS m/z 358 [M + H]+. 170 2-benzyl-4- (3,5-dimethyl- isoxazol-4- yl)phthalazin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.55-8.53 (m, 1H),7.83-7.76 (m, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.44-7.42 (m, 1H), 7.35-7.26 (m, 3H), 5.45 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H). 171 2-benzyl-4-((3,4,5- trimethoxy- phenyl) amino) phthalazin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.57-8.55 (m, 1H),7.84-7.76 (m, 3H), 7.41 (d, J = 6.8 Hz, 2H), 7.32-7.22 (m, 3H), 6.69 (s,2H), 6.40 (s, 1H), 5.38 (s, 2H), 3.81 (s, 3H), 3.70 (s, 6H); ESI MS m/z418 [M + 1]+. 172 2-benzyl-4- ((3,4,5- trimethoxy- phenyl) amino)isoquinolin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.2 Hz,1H), 7.61-7.68 (m, 2H), 7.54 (ddd, J = 8.2, 5.6, 2.7 Hz, 1H), 7.27- 7.35(m, 5H), 7.17 (s, 1H), 5.85 (s, 2H), 5.23 (s, 2H), 5.10 (s, 1H), 3.75(s, 3H), 3.65 (s, 6H); ESI MS m/z 417 [M + H]+. 173 6-benzyl-8- (3,5-dimethyl- isoxazol-4- yl)-1,6- naphthyridin- 5(6H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.92 (dd, J = 4.5, 1.9Hz, 1H), 8.78 (dd, J = 8.0, 1.9 Hz, 1H), 7.47 (dd, J = 8.0, 4.5 Hz, 1H),7.30- 7.41 (m, 5H), 7.20 (s, 1H), 5.27 (s, 2H), 2.25 (s, 3H), 2.11 (s,3H); ESI MS m/z 332 [M + H]+. 174 7-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-1,7- naphthyridin- 8(7H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3): δ 8.92-9.00 (m, 1H),7.52-7.60 (m, 2H), 7.29-7.42 (m, 5H), 7.04 (s, 1H), 5.26-5.43 (m, 2H),2.22 (s, 3H), 2.04 (s, 3H); ESI MS m/z 332.0 [M + H]+. 175 2-benzyl-4-(3,5- dimethyl- isoxazol-4- yl)-2,7- naphthyridin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.75 (d,J = 5.4 Hz, 1H), 7.31-7.41 (m, 5H), 7.16 (s, 1H), 7.02 (d, J = 5.4 Hz,1H), 5.26 (s, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MS m/z 332 [M + H]+.176 2-benzyl-4- (3,5- dimethyl- isoxazol-4- yl)-2,6- naphthyridin-1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 5.4 Hz,1H), 8.65 (s, 1H), 8.30 (d, J = 5.4 Hz, 1H), 7.30- 7.40 (m, 5H), 7.04(s, 1H), 5.26 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H); ESI MS m/z 332 [M +H]+. 177 2-benzyl-4- (2,3,4- trimethoxy- phenyl) phthalazin- 1(2H)-one

No general proce- dure 1H NMR (400 MHz, CDCl3) 8.51 (d, J = 7.5 Hz, 1H),7.79-7.69 (m, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H),7.36-7.30 (m, 1H), 7.30-7.24 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.74 (s,1H), 6.63 (d, J = 8.6 Hz, 1H), 5.47 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H);ESI MS m/z 389 [M + H]+. 178 6-(4- hydroxy- phenyl)-2-(1- phenylethyl)pyridazin- 3(2H)-one

A 1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.96 (d, J = 9.9 Hz, 1H),7.74 (d, J = 8.7 Hz, 2H), 7.44-7.19 (m, 5H), 6.99 (d, J = 9.9 Hz, 1H),6.84 (d, J = 8.7 Hz, 2H), 6.24 (q, J = 8.1 Hz, 1H), 1.75 (d, J = 7.2 Hz,3H); ESI m/z 293 [M + H]+. 179 2-benzyl-6-(4- methyl-3- oxopiperazin-1-yl) pyridazin- 3(2H)-one

B 1H NMR (300 MHz, CDCl3) δ 7.42-7.45 (m, 2H); 7.27-7.35 (m, 3H); 7.04(d, J = 9.9 Hz, 1H); 6.92 (d, J = 9.9 Hz, 1H); 5.19 (s, 2H); 3.93 (s,2H); 3.52-3.56 (m, 2H); 3.40- 3.43 (m, 2H); 3.01 (s, 3H); ESI MS m/z 299[M + H]+. 180 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-(4-fluorobenzyl) pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.45-7.40 (m, 2H), 7.21-7.15 (m, 2H), 7.13(d, J = 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 5.29 (s, 2H), 5.11 (s,2H), 2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 314 [M + H]+ 181 3-chloro-5-(3,5- dimethyl- isoxazol-4- yl)-1-(4- fluorobenzyl) pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 8.03 (s, 1H), 7.49-7.45 (m,2H), 7.23-7.16 (m, 2H), 5.17 (s, 2H), 3.37 (s, 3H), 2.20 (s, 3H); ESIm/z 333 [M + H]+. 182 5-(3,5- dimethyl- isoxazol-4- yl)-1-(4-fluorobenzyl)- 3- (phenylamino) pyridin-2(1H)- one

J 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.51-7.46 (m, 2H), 7.40 (d,J = 2.1 Hz, 1H), 7.28- 7.27 (m, 4H), 7.23-7.17 (m, 2H), 6.97 (d, J = 2.1Hz, 1H), 6.95-6.93 (m, 1H), 5.19 (s, 2H), 2.19 (s, 3H), 1.99 (s, 3H);ESI m/z 390 [C23H20FN3O2 + H]+. 183 3-(azetidin-1- yl)-1-benzyl- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.25-7.38 (m, 5H),7.21 (d, J = 2.2 Hz, 1H), 6.07 (d, J = 2.2 Hz, 1H), 5.07 (s, 2H), 3.89(t, J = 7.2 Hz, 4H), 2.34 (s, 3H), 2.18 (t, J = 7.2 Hz, 2H), 2.17 (s,3H); ESI m/z 336 [M + H]+. 184 1-benzyl-5- (3,5- dimethyl- isoxazol-4-yl)-3-((1- methyl-1H- pyrazol-3- yl)amino) pyridin- 2(1H)-one

J 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J = 2.0 Hz, 1H), 7.46 (s, 1H),7.37-7.26 (m, 5H), 7.21 (d, J = 1.5 Hz, 1H), 6.63 (d, J = 1.5 Hz, 1H),5.83 (d, J = 2.0 Hz, 1H), 5.25 (s, 2H), 3.80 (s, 3H), 2.34 (s, 3H), 2.23(s, 3H). ESI MS m/z 376 [M + H]+. 185 3-(1-benzyl- 5-(3,5- dimethyl-isoxazol-4- yl)-2-oxo- 1,2-dihydro- pyridin-3- yl)benzamide

I 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.12 (m, 1H), 8.05 (d, J = 2.7 Hz,1H), 7.98 (s, 1H), 7.92-7.88 (m, 1H), 7.83- 7.79 (m, 1H), 7.75 (d, J =2.4 Hz, 1H), 7.49-7.27 (m, 7H), 5.24 (s, 2H), 2.41 (s, 3H), 2.24 (s,3H); ESI MS m/z 400 [M + H]+. 186 1-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-3-(ethyl- amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.26 (m, 5H), 7.08 (d, J = 2.1 Hz,1H), 6.14 (d, J = 2.4 Hz, 1H), 5.49 (t, J = 6.0 Hz, 1H), 5.14 (s, 2H),3.11-3.02 (m, 2H), 2.36 (s, 3H), 2.19 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H);ESI MS m/z 324 [M + H]+. 187 1-benzyl-5- (3-(methoxy- methyl)-5- methyl-isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, DMSO-d6) δ 7.91 (d, J = 2.4 Hz, 1H), 7.53 (dd, J =9.3, 2.4 Hz, 1H), 7.39- 7.27 (m, 5H), 6.52 (d, J = 9.3 Hz, 1H), 5.14 (s,2H), 4.41 (s, 2H), 3.18 (s, 3H), 2.40 (s, 3H); ESI m/z 311 [M + H]+. 1881-(4-chloro- benzyl)-5- (3,5- dimethyl- isoxazol-4- yl)-3- (phenyl-amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.44 (s, 4H), 7.40 (d, J =2.1 Hz, 1H), 7.29-7.27 (m, 4H), 6.98 (d, J = 2.1 Hz, 1H), 6.95-6.91 (m,1H), 5.20 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 406 [M + H]+. 1893-amino-1- benzyl-5- (3-(hydroxy- methyl)-5- methyl- isoxazol-4-yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHZ, DMSO-d6) δ 7.25-7.37 (m, 5H),7.18 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 5.42 (t, J = 5.6 Hz,1H), 5.25 (s, 2H), 5.12 (s, 2H), 4.44 (d, J = 5.6 Hz, 2H), 2.37 (s, 3H);ESI m/z 312 [M + H]+ 190 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-morpholino- pyridin- 2(1H)-one

M 1H NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 6.91 (br s, 1H), 6.71 (brs, 1H), 5.19 (s, 2H), 3.96-3.93 (m, 4H), 3.27 (s, 4H), 2.31 (s, 3H),2.18 (s, 3H); ESI m/z 366 [M + H]+. 191 1-benzyl-3- (benzyloxy)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.52 (d, J = 2.1 Hz, 1H), 7.45-7.32 (m,10H), 6.91 (d, J = 2.1 Hz, 1H), 5.15 (s, 2H), 5.07 (s, 2H), 2.31 (s,3H), 2.14 (s, 3H); ESI m/z 387 [C24H22N2O3 + H]+. 192 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-3- (isopropyl- amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 7.38-7.26 (m, 5H), 7.09 (d, J = 2.1 Hz,1H), 6.18 (d, J = 2.1 Hz, 1H), 5.17 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H),3.57-3.30 (m, 1H), 2.36 (s, 3H), 2.20 (s, 3H), 1.14 (d, J = 6.3 Hz, 6H);ESI MS m/z 338 [M + H]+. 193 1-benzyl-5- (3,5- dimethyl- isoxazol-4-yl)-3- (pyridin-2- ylamino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H),8.20 (dd, J = 5.1, 1.2 Hz, 1H), 7.62-7.56 (m, 1H), 7.49 (d, J = 2.1 Hz,1H), 7.43-7.26 (m, 6H), 6.83- 6.79 (m, 1H), 5.24 (s, 2H), 2.42 (s, 3H),2.25 (s, 3H); ESI MS m/z 373 [M + H]+. 194 1-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-3- (pyridin-3- ylamino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, J = 2.7 Hz, 1H), 8.12 (s, 1H),8.10 (d, J = 1.5 Hz, 1H), 7.68-7.65 (m, 1H), 7.45- 7.26 (m, 7H), 7.02(d, J = 2.1 Hz, 1H), 5.22 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESI MSm/z 373 [M + H]+. 195 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-(pyridin-4- ylamino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.24 (dd, J = 1.5, 4.8 Hz,2H), 7.60 (d, J = 2.1 Hz, 1H), 7.43-7.30 (m, 6H), 7.15 (dd, J = 1.5, 4.8Hz, 2H), 5.22 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H); ESI MS m/z 373 [M +H]+. 196 1-benzyl-5- (3,5- dimethyl- isothiazol-4- yl)pyridin- 2(1H)-one

F 1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, J = 2.1 Hz, 1H), 7.47 (dd, J =9.3, 2.4 Hz, 1H), 7.36- 7.29 (m, 5H), 6.52 (d, J = 9.3 Hz, 1H), 5.14 (s,2H), 2.39 (s, 3H), 2.29 (s, 3H); ESI m/z 297 [M + H]+. 197 1-(4-chlorobenzyl)- 5-(3,5- dimethyl-4H- 1,2,4-triazol- 4-yl) pyridin-2(1H)-one

No general proce- dure 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, J = 2.7 Hz,1H), 7.58 (dd, J = 9.6, 2.4 Hz, 1H), 7.45- 7.36 (m, 4H), 6.55 (d, J =9.6 Hz, 1H), 5.08 (s, 2H), 2.19 (s, 6H); ESI m/z 315 [M + H]+. 1981-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-2-oxo- 1,2- dihydro-pyridine-3- carbonitrile

No general proce- dure 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 2.6 Hz,1H), 7.45-7.33 (m, 6H), 5.21 (s, 2H), 2.28 (s, 3H), 2.13 (s, 3H); ESI MSm/z 306 [M + H]+ 199 methyl 4- (1-(4-chloro- benzyl)- 6-oxo-l,6-dihydro- pyridin-3- yl)-5-methyl- isoxazole- 3-carboxylate

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 2.3 Hz,1H), 7.50 (dd, J = 2.5, 9.3 Hz, 1H), 7.33- 7.47 (m, 4H), 6.47 (d, J =9.3 Hz, 1H), 5.09 (s, 2H), 3.79 (s, 3H), 2.44 (s, 3H); ESI m/z 359 [M +H]+. 200 N-(1-benzyl- 5-(3,5- dimethyl- isoxazol- 4-yl)-2-oxo-1,2-dihydro- pyridin-3- yl)methane- sulfonamide

No general proce- dure 1H NMR (500 MHz, DMSO-d6): δ 9.02 (s, 1H), 7.78(d, J = 3.5 Hz, 1H), 7.38-7.26 (m, 6H), 5.20 (s, 2H), 3.30 (s, 3H), 2.42(s, 3H), 2.20 (s, 3H). ESI MS m/z 374 [M + H]+. 201 2-benzyl-6- (((3,5-dimethyl- isoxazol-4- yl)methyl) amino) pyridazin- 3(2H)-one

No general proce- dure 1H NMR (300 MHz, DMSO-d6) δ 7.41-7.38 (m, 2H),7.35-7.27 (m, 3H), 6.86 (d, J = 16.0 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H),5.20 (s, 2H), 4.09 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H); ESI m/z 311 [M +H]+. 202 4-(1-(4- chlorobenzyl)- 6-oxo-1,6- dihydro- pyridin- 3-yl)-5-methyl- isoxazole-3- carboxamide

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.95(d, J = 2.3 Hz, 1H), 7.82 (s, 1H), 7.45 (dd, J = 2.5, 9.3 Hz, 1H), 7.34-7.44 (m, 4H), 6.45 (d, J = 9.3 Hz, 1H), 5.09 (s, 2H), 2.42 (s, 3H); ESIm/z 344 [M + H]+. 203 3-amino-1- (4-chloro-3- fluorobenzyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

D 1H NMR (300 MHz, CDCl3) δ 7.40-7.35 (m, 1H), 7.11 (d, J = 9.6 Hz, 1H),7.06 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz,1H), 5.15 (s, 2H), 4.38 (s, 2H), 2.33 (s, 3H), 2.20 (s, 3H); ESI m/z 348[M + H]+; 204 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-(1H-imidazol-1- yl)pyridin- 2(1H)-one

J 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 7.45-7.37 (m, 6H), 7.28 (d, J= 2.4 Hz, 1H), 7.19 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 5.28 (s, 2H),2.33 (s, 3H), 2.19 (s, 3H); ESI m/z 347 [M + H]+. 205 3-amino-1-(4-chloro-2- fluorobenzyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin-2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.32-7.45 (m, 4H),7.19 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 5.43 (t, J = 5.6 Hz,1H), 5.27 (s, 2H), 5.11 (s, 2H), 4.44 (d, J = 5.6 Hz, 2H), 2.38 (s, 3H);ESI m/z 346 [M + H]+. 206 3-amino-1-(4- chloro-2- fluorobenzyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (300 MHz, CDCl3) δ 7.51-7.46 (m, 1H), 7.16-7.10 (m, 2H),6.72-6.71 (m, 1H), 6.38 (d, J = 2.1 Hz, 1H), 5.16 (s, 2H), 4.32 (s, 2H),2.35 (s, 3H), 2.21 (s, 3H); ESI m/z 348 [M + H]+. 207 3-amino-1-(2-chloro-4- fluorobenzyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin-2(1H)-one

N 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J = 8.6, 6.0 Hz, 1H), 7.17 (dd, J= 8.3, 2.6 Hz, 1H), 7.02- 6.97 (m, 1H), 6.67 (d, J = 2.2 Hz, 1H), 6.41(d, J = 2.2 Hz, 1H), 5.27 (s, 2H), 4.36 (br s, 2H), 2.33 (s, 3H), 2.19(s, 3H); ESI m/z 348 [M + H]+; 208 1-benzyl-3- (cyclopentyl- amino)-5-(3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 7.38-7.26 (m, 5H), 7.10 (d, J = 2.1 Hz,1H), 6.17 (d, J = 1.8 Hz, 1H), 5.29 (d, J = 6.6 Hz, 1H), 5.13 (s, 2H),3.71-3.65 (m, 1H), 2.36 (s, 3H), 2.20 (s, 3H), 1.96- 1.88 (m, 2H),1.67-1.45 (m, 6H); ESI MS m/z 364 [M + H]+. 209 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-3- hydroxy- pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.39 (d, J = 2.1 Hz, 1H),7.37-7.27 (m, 5H), 6.77 (d, J = 2.1 Hz, 1H), 5.17 (s, 2H), 2.35 (s, 3H),2.18 (s, 3H); ESI m/z 297 [C17H16N2O3 + H]+. 210 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-3- methoxy- pyridin- 2(1H)-one

N 1H NMR (300 MHz, CDCls) δ 7.33-7.24 (m, 5H), 6.75 (s, 1H), 6.45 (s,1H), 5.22 (s, 2H), 3.85 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H); ESI m/z 311(C18H18N2O3 + H]+. 211 3-amino-1- (3,4- difluoro- benzyl)-5- (3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSO-d6): δ 7.50-7.32 (m, 2H), 7.24-7.14 (m, 1H),7.08 (d, J = 2.5 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 5.31 (s, 2H), 5.10(s, 2H), 2.35 (s, 3H), 2.18 (s, 3H). ESI MS m/z 332 [M + H]+. 2123-amino-1- (3-chloro-4- fluorobenzyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSO-d6): δ 7.62 (d, J = 3.5 Hz, 1H), 7.45-7.38 (m,2H), 7.17 (d, J = 3.5 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), 5.31 (s, 2H),5.10 (s, 2H), 2.40 (s, 3H), 2.18 (s, 3H). ESI MS m/z 348 [M + H]+. 2133-amino-1- (3,4- dichloro- benzyl)-5- (3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSO-d6): δ 7.66-7.62 (m, 1H), 7.61 (s, 1H), 7.34(dd, J = 13, 3.5 Hz, 1H), 7.17 (d, J = 3.5 Hz, 1H), 6.45 (d, J = 3.5 Hz,1H), 5.31 (s, 2H), 5.12 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H). ESI MS m/z365 [M + H]+. 214 1-benzyl-5-(5- (hydroxy- methyl)-3- methyl-isoxazol-4- yl)pyridin- 2(1H)-one

F 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J = 2.4 Hz, 1H), 7.54 (dd, J =9.3, 2.4 Hz, 1H), 7.36- 7.29 (m, 5H), 6.52 (d, J = 9.3 Hz, 1H), 5.62 (d,J = 6.0 Hz, 1H), 5.13 (s, 2H), 4.47 (d, J = 6.0 Hz, 2H), 2.23 (s, 3H);ESI m/z 297 [M + H]+. 215 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-(thiazol-2- ylmethyl) pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J = 3.3 Hz, 1H), 7.69 (d, J = 3.3Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 5.45 (s,2H), 5.34 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 303 [M + H]+. 2164-((3-amino- 5-(3,5- dimethyl- isoxazol-4- yl)-2- oxopyridin- 1(2H)-yl)methyl) benzonitrile

N 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4Hz, 2H), 7.15 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 5.31 (s,2H), 5.22 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z 321 [C18H16N4O2 +H]+. 217 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-((3,5- dimethyl-isoxazol-4- yl)amino) pyridin- 2(1H)-one

M 1H NMR (300 MHz, DMSO-d6) δ 7.45-7.30 (m, 5H), 7.26 (d, J = 2.1 Hz,1H), 7.20 (s, 1H), 6.91 (d, J = 2.1 Hz, 1H), 5.19 (s, 2H), 2.29 (s, 3H),2.22 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H); ESI m/z 391 [M + H]+; 2185-(3,5- dimethyl- isoxazol-4- yl)-1-(4- vinylbenzyl) pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 2.4 Hz,1H), 7.50 (dd, J = 2.5, 9.3 Hz, 1H), 7.30- 7.50 (m, 4H), 6.71 (dd, J =10.9, 17.6 Hz, 1H), 6.51 (d, J = 9.3 Hz, 1H), 5.81 (dd, J = 0.7, 17.6Hz, 1H), 5.25 (dd, J = 0.63, 10.9 Hz, 1H), 5.11 (s, 2H), 2.35 (s, 3H),2.18 (s, 3H); ESI m/z 307 [M + H]+. 219 3-amino-5- (3,5- dimethyl-isoxazol-4- yl)-1- (thiophen-3- ylmethyl) pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.50 (d, J = 4.9 Hz, 1H), 7.45 (d, J = 1.2Hz, 1H), 7.14 (dd, J = 4.9, 1.2 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.43(d, J = 2.3 Hz, 1H), 5.28 (s, 2H), 5.11 (s, 2H), 2.34 (s, 3H), 2.17 (s,3H); ESI m/z 302 [M + H]+; 220 3-amino-5- (3,5- dimethyl- isoxazol-4-yl)-1-(4- methoxy- benzyl) pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 2.4Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 2.4 Hz, 1H), 5.26 (s,2H), 5.05 (s, 2H), 3.72 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); ESI m/z 326[C18H19N3O3 + H]+. 221 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-(pyridazin-3- ylamino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H),8.71 (d, J = 1.2 Hz, 1H), 7.63-7.49 (m, 2H), 7.48- 7.30 (m, 6H), 5.26(s, 2H), 2.41 (s, 3H), 2.24 (s, 3H); ESI m/z 374 [C21H19N5O2 + H]+. 2223-amino-1- ((5-chloro- thiophen-2- yl)methyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.15 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 3.9Hz, 1H), 6.99 (d, J = 3.6 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 5.39 (s,2H), 5.19 (s, 2H), 2.36 (s, 3H), 2.18 (s, 3H); ESI m/z 336 [M + H]+. 2231-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-((5- fluoro- pyridin-3-yl)amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.40 (s, 1H), 8.05 (d, J =2.4 Hz, 1H), 7.56-7.50 (m, 3H), 7.44-7.30 (m, 5H), 7.21 (d, J = 2.1 Hz,1H), 5.23 (s, 2H), 2.38 (s, 3H), 2.21 (s, 3H); ESI m/z 391 [M + H]+. 2243-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1- methyl- pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 6.97 (d, J = 2.2 Hz,1H), 6.42 (d, J = 2.2 Hz, 1H), 5.22 (s, 2H), 3.47 (s, 3H), 2.35 (s, 3H),2.18 (s, 3H); ESI m/z 220 [M + H]+. 225 4-(1-(4- chlorobenzyl)-6-oxo-1,6- dihydro- pyridin- 3-yl)-5- methyl- isoxazole-3- carboxylicacid

No general proce- dure 1H NMR (500 MHz, CD3OD) δ 7.84 (d, J = 2.4 Hz,1H), 7.56 (dd, J = 2.4, 9.3 Hz, 1H), 7.35 (s, 4H), 6.60 (d, J = 9.3 Hz,1H), 5.19 (s, 2H), 2.40 (s, 3H); ESI m/z 345 [M + H]+. 226 3-amino-5-(3,5- dimethyl- isoxazol-4- yl)-1-(4- (trifluoro- methoxy) benzyl)pyridin- 2(1H)-one

N 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2Hz, 2H), 6.58 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 5.21 (s,2H), 4.38 (s, 2H), 2.31 (s, 3H), 2.18 (s, 3H); ESI MS m/z 380 [M + H]+227 3-amino-1-(2- chlorobenzyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

N 1H NMR (300 MHz, CDCl3) δ 7.55-7.38 (m, 2H), 7.32-7.23 (m, 2H), 6.64(d, J = 2.1 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 4.37 (s, 2H), 2.31 (s,3H), 2.18 (s, 3H); ESI MS m/z 330 [M + H]+ 228 3-amino-5- (3,5-dimethyl- isoxazol-4- yl)-1-(4- (trifluoro- methyl) benzyl) pyridin-2(1H)-one

N 1H NMR (500 MHz, DMSO-d6) δ 7.72 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.0Hz, 2H), 7.14 (d, J = 2.5 Hz, 1H), 6.46 (d, J = 2.5 Hz, 1H), 5.29 (s,2H), 5.23 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 364 [M + H]+. 2291-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-2-oxo- 1,2-dihydro-pyridine-3- carboxylic acid

No general proce- dure 1H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 7.49-7.39(m, 4H), 7.36- 7.33 (m, 2H), 5.28 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H);ESI MS m/z 325 [M + H]+ 230 1-benzyl-5- (3,5- dimethyl- isoxazol-4-yl)-2-oxo- 1,2-dihydro- pyridine-3- carboxamide

No general proce- dure 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 8.45 (d,J = 2.7 Hz, 1H), 7.44-7.30 (m, 6H), 5.75 (s, 1H), 5.26 (s, 2H), 2.30 (s,3H), 2.15 (s, 3H); ESI MS m/z 324 [M + H]+ 231 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-3-((5- methoxy- pyridin-3- yl)amino) pyridin-2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J = 2.1 Hz, 1H), 8.09 (s, 1H),7.85 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.44-7.26 (m, 6H),7.09 (dd, J = 2.1, 2.1 Hz, 1H), 5.22 (s, 2H), 3.78 (s, 3H), 2.38 (s,3H), 2.21 (s, 3H); ESI m/z 403 [M + H]+. 232 5-((1-benzyl- 5-(3,5-dimethyl- isoxazol-4- yl)-2-oxo-1,2- dihydro- pyridin-3- yl)amino)picolinonitrile

J 1H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H),7.79 (d, J = 8.4 Hz, 1H), 7.67-7.60 (m, 2H), 7.43- 7.28 (m, 6H), 5.23(s, 2H), 2.38 (s, 3H), 2.22 (s, 3H); ESI m/z 398 [M + H]+. 2334-amino-2- (4-chloro- benzyl)-6- (3,5- dimethyl- isoxazol-4-yl)pyridazin- 3(2H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.33 (m, 4H), 6.63 (s, 2H), 6.42 (s,1H), 5.24 (s, 2H), 2.44 (s, 3H), 2.23 (s, 3H); ESI m/z 331 [M + H]+. 2341-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3-((6- methoxy- pyridin-3-yl)amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J = 2.7 Hz, 1H), 7.80 (s, 1H),7.67 (dd, J = 9.2, 2.1 Hz, 1H), 7.44-7.28 (m, 6 H), 6.78 (d, J = 8.7 Hz,1H), 6.64 (s, 1H), 5.21 (s, 2H), 3.81 (s, 3H), 2.33 (s, 3H), 2.15 (s,3H); ESI m/z 403 [C23H22N4O3 + H]+. 235 1-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-3- (pyrazin-2- ylamino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.68 (d, J = 1.2 Hz, 1H),8.55 (d, J = 2.1 Hz, 1H), 8.19-8.17 (m, 1H), 7.98 (d, J = 2.7 Hz, 1H),7.58 (d, J = 2.4 Hz, 1H), 7.40- 7.33 (m, 5H), 5.25 (s, 2H), 2.41 (s,3H), 2.24 (s, 3H); ESI m/z 374 [C21H19N5O2 + H]+. 236 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-3- (pyrimidin-5- ylamino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 2H), 8.70 (s, 1H), 8.33 (s, 1H),7.52 (d, J = 2.1 Hz, 1H), 7.43-7.28 (m, 5H), 7.17 (d, J = 2.1 Hz, 1H),5.23 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H); ESI m/z 374 [C21H19N5O2 + H]+.237 3-amino-1-(4- (azetidin-1- yl)benzyl)- 5-(3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.23 (d, J = 8.5 Hz,2H), 7.04 (d, J = 2.2 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 6.35 (d, J =8.5 Hz, 2H), 5.23 (s, 2H), 4.98 (s, 2H), 3.74 (t, J = 7.1 Hz, 4H), 2.33(s, 3H), 2.26 (quintet, J = 7.1 Hz, 2H), 2.16 (s, 3H); ESI m/z 351 [M +H]+. 238 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-(4- morpholino-benzyl) pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.27 (d, J = 8.7 Hz,2H), 7.07 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.41 (d, J =2.2 Hz, 1H), 5.24 (s, 2H), 5.01 (s, 2H), 3.70 (t, J = 4.8 Hz, 4H), 3.06(t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 381 [M + H]+.239 1-benzyl-5- (3,5- dimethyl- isoxazol-4- yl)-3- (pyrrolidin-3-ylamino) pyridin- 2(1H)-one

M 1H NMR (500 MHz, DMSO-d6) δ 9.12 (br s, 1H), 8.85 (br s, 1H), 7.38-7.33 (m, 4H), 7.30-7.28 (m, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.28 (d, J =2.0 Hz, 1H), 5.16-5.15 (m, 2H), 4.13-4.05 (m, 1H), 3.41-3.34 (m, 1H),3.34- 3.26 (m, 1H), 2.21-2.19 (m, 2H), 2.37 (s, 3H), 2.21 (s, 3H),2.20-2.13 (m, 1H), 2.00-1.92 (m, 1H); ESI m/z 365 [M + H]+; 2403-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-((3- methyl- isoxazol-5-yl)methyl) pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSO-d6) δ 7.07 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0Hz, 1H), 6.23 (s, 1H), 5.31 (s, 2H), 5.26 (s, 2H), 2.37 (s, 3H), 2.19(s, 6H); ESI m/z 301 [M + H]+. 241 3-amino-1-(4- bromobenzyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHZ, DMSO-d6) δ 7.54 (d, J = 8.4 Hz,2H), 7.31 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 2.2 Hz, 1H), 6.45 (d, J =2.2 Hz, 1H), 5.27 (s, 2H), 5.10 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H); ESIm/z 374 [M + H]+. 242 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-(4-isopropyl- benzyl) pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.27 (d, J = 8.1 Hz,2H), 7.20 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 2.2 Hz, 1H), 6.43 (d, J =2.2 Hz, 1H), 5.25 (s, 2H), 5.08 (s, 2H), 2.84 (octet, J = 6.9 Hz, 1H),2.34 (s, 3H), 2.17 (s, 3H), 1.17 (d, J = 6.9 Hz, 6H); ESI m/z 338 [M +H]+. 243 1-(4-chloro- benzyl)-5- (3,5- dimethyl- isoxazol-4-yl)-3-((2,2,2- trifluoroethyl) amino) pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 7.36-7.45 (m, 4H),7.23 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 1.7 Hz, 1H), 6.11 (t, J = 7.1 Hz,1H), 5.14 (s, 2H), 3.93-4.04 (m, 2H), 2.35 (s, 3H), 2.18 (s, 3H); ESIm/z 412 [M + H]+. 244 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-((6-methyl- pyridin-2- yl)methyl) pyridin- 2(1H)-one

N 1H NMR (500 MHz, CDCl3) δ 7.55 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.7Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.40 (d, J= 2.1 Hz, 1H), 5.26 (s, 2H), 4.31 (s, 2H), 2.51 (s, 3H), 2.35 (s, 3H),2.21 (s, 3H); ESI MS m/z 311 [M + H]+ 245 1-benzyl-5- (3,5- dimethyl-isoxazol-4- yl)-3-((6- methyl- pyridin-3- yl)amino) pyridin- 2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.41 (d, J = 2.7 Hz, 1H), 7.91 (s, 1H),7.58 (dd, J = 8.3 Hz, 3.0 Hz, 1H), 7.40-7.35 (m, 6H), 7.15 (d, J = 8.4Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 5.22 (s, 2H), 2.37 (d, J = 11.1 Hz,6H), 2.18 (s, 3H); ESI m/z 387 [C23H22N4O2 + H]+. 246 1-benzyl-5- (3,5-dimethyl- isoxazol-4- yl)-3-((5- methyl- pyridin-3- yl)amino) pyridin-2(1H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 8.34 (d, J = 2.4 Hz, 1H), 8.02 (s, 1H),7.96 (s, 1H), 7.50-7.30 (m, 7H), 7.04 (d, J = 2.1 Hz, 1H), 5.22 (s, 2H),2.38 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H); ESI m/z 387 [M + H]+. 2471-((1H-indol- 4-yl)methyl)- 3-amino-5- (3,5- dimethyl- isoxazol-4-yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H),7.31-7.36 (m, 2H), 7.03 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H),6.87 (d, J = 7.0 Hz, 1H), 6.59-6.62 (m, 1H), 6.43 (d, J = 2.3 Hz, 1H),5.40 (s, 2H), 5.28 (s, 2H), 2.25 (s, 3H), 2.08 (s, 3H); ESI m/z 335 [M +H]+. 248 2-benzyl-6- (3,5- dimethyl- isoxazol-4- yl)-4- (pyridin-3-ylamino) pyridazin- 3(2H)-one

J 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H),8.32 (dd, J = 4.8, 1.5 Hz, 1H), 7.86 (dd, J = 8.1, 1.5 Hz, 1H),7.42-7.30 (m, 6H), 6.81 (s, 1H), 5.35 (s, 2H), 2.43 (s, 3H), 2.23 (s,3H); ESI m/z 374 [M + H]+. 249 4-(1-benzyl- 6-oxo-1,6- dihydro-pyridin-3- yl)-N- methoxy-N,5- dimethyl- isoxazole-3- carboxamide

F 1H NMR (500 MHz, CDCl3) δ 7.38-7.35 (m, 1H), 7.33-7.30 (m, 6H), 6.76(d, J = 9.3 Hz, 1H), 5.16 (s, 2H), 3.66 (s, 3H), 3.21 (s, 3H), 2.39 (s,3H); ESI m/z 354 [M + H]+; 250 4-amino-2- benzyl-6-(3,5- dimethyl-isoxazol-4- yl)pyridazin- 3(2H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.34-7.26 (m, 5H), 6.62 (s, 2H), 6.41 (s,1H), 5.25 (s, 2H), 2.43 (s, 3H), 2.23 (s, 3H); ESI m/z 297 [M + H]+. 2513-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-((2,5- dimethyl-thiophen-3- yl)methyl) pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 6.99 (d, J = 2.1 Hz, 1H), 6.62 (s, 1H),6.42 (d, J = 2.1 Hz, 1H), 5.28 (s, 2H), 4.94 (s, 2H), 2.43 (s, 3H), 2.35(s, 3H), 2.30 (s, 3H), 2.17 (s, 3H); ESI m/z 330 [M + H]+. 2523-amino-1- ((5-chloro- pyridin-3- yl)methyl)- 5-(3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 1.5 Hz, 1H), 8.56 (d, J = 2.0Hz, 1H), 7.92 (s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz,1H), 5.32 (s, 2H), 5.16 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z 331[M + H]+. 253 3-amino-1- ((3-chloro- pyridin-4- yl)methyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSO-d6) δ 8.41 (d, J = 1.5 Hz, 1H), 7.96 (dd, J =8.0, 1.0 Hz, 1H), 7.36 (dd, J = 8.0, 7.5 Hz, 1H), 7.02 (d, J = 2.0 Hz,1H), 6.50 (d, J = 2.5 Hz, 1H), 5.36 (s, 2H), 5.17 (s, 2H), 2.36 (s, 3H),2.19 (s, 3H); ESI m/z 331 [M + H]+. 254 3-amino-1- ((3-chloro-pyridin-2- yl)methyl)- 5-(3,5- dimethyl- isoxazol-4- yl)pyridin-2(1H)-one

N 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H),7.09 (d, J = 2.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 2.5 Hz,1H), 5.34 (s, 2H), 5.24 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H); ESI m/z331[M + H]+. 255 3-amino-1- ((5-chloro- pyridin-2- yl)methyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, CD3OD) δ 8.52 (d, J = 2.3 Hz, 1H), 7.84 (dd, 8.4, 2.5Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.66 (d, J= 2.2 Hz, 1H), 5.33 (s, 2H), 2.41 (s, 3H), 2.25 (s, 3H); ESI MS m/z 331[M + H]+ 256 3-amino-1- (benzo[d] [1,3]dioxol- 5-ylmethyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, CD3OD) δ 6.98 (d, J = 2.2 Hz, 1H), 6.91-6.89 (m, 1H),6.89-6.85 (m, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H),5.92 (s, 2H), 5.15 (s, 2H), 2.35 (s, 3H), 2.20 (s, 3H); ESI MS m/z 340[M + H]+ 257 3-amino-1- (benzo[d] [1,3]dioxol- 4-ylmethyl)- 5-(3,5-dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

N 1H NMR (500 MHz, CD3OD) δ 6.99 (d, J = 2.2 Hz, 1H), 6.83- 6.80 (m,3H), 6.62 (d, J = 2.2 Hz, 1H), 5.98 (s, 2H), 5.22 (s, 2H), 2.37 (s, 3H),2.21 (s, 3H); ESI MS m/z 340 [M + H]+ 258 3-amino-5- (3,5- dimethyl-isoxazol-4- yl)-1-((6- methyl- pyridin-3- yl)methyl) pyridin- 2(1H)-one

N 1H NMR (500 MHz, DMSOd6) δ 8.46 (d, J = 2.0 Hz, 1H), 7.75 (dd, J =8.1, 2.3 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H),6.62 (d, J = 2.2 Hz, 1H), 5.25 (s, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 2.22(s, 3H); ESI MS m/z 311 [M + H]+ 259 methyl 4-(1- (4-chloro- benzyl)-6-oxo-1,6- dihydro- pyridin-3- yl)-3- methyl- isoxazole-5- carboxylate

F 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 2.4 Hz, 1H), 7.59 (dd, J =9.6, 2.4 Hz, 1H), 7.46- 7.37 (m, 4H), 6.50 (d, J = 9.6 Hz, 1H), 5.10 (s,2H), 3.78 (s, 3H), 2.29 (s, 3H); ESI m/z 359 [M + H]+. 260 4-(1-(4-chlorobenzyl)- 6-oxo-1,6- dihydro- pyridin- 3-yl)-3- methyl-isoxazole-5- carboxylic acid

F 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J = 2.1 Hz, 1H), 7.58 (dd, J =9.3, 2.7 Hz, 1H), 7.40 (s, 4H), 6.39 (d, J = 9.3 Hz, 1H), 5.09 (s, 2H),2.17 (s, 3H); ESI m/z 345 [M + H]+. 261 4-((3-amino- 5-(3,5- dimethyl-isoxazol-4- yl)-2- oxopyridin- 1(2H)- yl)methyl)-3- fluoro- benzonitrile

N 1H NMR (500 MHz, DMSO-d6) δ 7.88 (dd, J = 5.0, 1.5 Hz, 1H), 7.68 (dd,J = 8.0, 1.5 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 2.0 Hz,1H), 6.49 (d, J = 2.5 Hz, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 2.36 (s, 3H),2.19 (s, 3H); ESI m/z 339 [M + H]+. 262 4-((3-amino- 5-(3,5- dimethyl-isoxazol-4- yl)-2- oxopyridin- 1(2H)- yl)methyl)-2- fluoro- benzonitrile

N 1H NMR (500 MHz, DMSO-d6): δ 7.91 (dd, J = 8, 7 Hz, 1H), 7.45 (dd, J =15, 1 Hz, 1H), 7.30 (dd, J = 8, 1.5 Hz, 1H), 7.14 (d, J = 2 Hz, 1H),6.47 (d, J = 2 Hz, 1H), 5.32 (s, 2H), 5.22 (s, 2H), 2.36 (s, 3H), 2.19(s, 3H). ESI MS m/z 339 [M + H]+. 263 3-amino-5- (3,5- dimethyl-isoxazol-4- yl)-1-(1- phenylethyl) pyridin- 2(1H)-one

N 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.35 (m, 4H), 7.33-7.27 (m, 1H), 6.80(d, J = 2.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 6.28 (q, J = 7.2 Hz, 1H),5.30 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H); ESIm/z 310 [M + H]+. 264 5-((3-amino- 5-(3,5- dimethyl- isoxazol-4- yl)-2-oxopyridin- 1(2H)- yl)methyl) thiophene-2- carbonitrile

N 1H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 3.9Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 5.40-5.30(m, 4H), 2.36 (s, 3H), 2.19 (s, 3H); ESI m/z 327 [M + H]+. 265 4-(1-(4-chlorobenzyl)- 6-oxo-1,6- dihydro- pyridin- 3-yl)-N,3- dimethyl-isoxazole-5- carboxamide

F 1H NMR (300 MHz, DMSO-d6) δ 8.83 (q, J = 4.5 Hz, 1H), 8.07 (d, J = 2.4Hz, 1H), 7.54 (dd, J = 9.3, 2.4 Hz, 1H), 7.44- 7.38 (m, 4H), 6.45 (d, J= 9.6 Hz, 1H), 5.10 (s, 2H), 2.73 (d, J = 4.5 Hz, 3H), 2.27 (s, 3H); ESIm/z 358 [M + H]+. 266 3-(amino- methyl)-1- benzyl-5- (3,5- dimethyl-isoxazol-4- yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (300 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 7.24(s, 1H), 7.10 (d, J = 2.5 Hz, 1H), 5.19 (s, 2H), 3.89 (s, 2H), 3.17 (s,2H), 2.31 (s, 3H), 2.15 (s, 3H); ESI MS m/z 310 [M + H]+ 267 3-amino-5-(3,5- dimethyl- isoxazol-4- yl)-1-(4- iodobenzyl) pyridin- 2(1H)-one

O 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1Hz, 2H), 7.11 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 5.29 (s,2H), 5.08 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H); ESI m/z 422 [M + H]+. 2681-benzyl-5-(5- oxopyrrolidin- 3-yl)pyridin- 2(1H)-one

No general proce- dure 1H NMR (300 MHz, CDCl3) δ 7.39-7.26 (m, 6H), 7.10(d, J = 2.7 Hz, 1H), 6.67 (d, J = 9.6 Hz, 1H), 5.63 (br.s, 1H), 5.13 (s,2H), 3.66 (dd, J = 9.3, 9.0 Hz, 1H), 3.46-3.38 (m, 1H), 3.25 (dd, J =9.3, 7.2 Hz, 1H), 2.61 (dd, J = 16.8, 9.0 Hz, 1H), 2.30 (dd, J = 9.3,8.7 Hz, 1H); ESI m/z 269 [M + H]+. 269 4-(1-(3- amino- 5-(3,5- dimethyl-isoxazol-4- yl)-2- oxopyridin- 1(2H)- yl)ethyl) benzonitrile

N 1H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4Hz, 2H), 6.91 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 6.25 (q, J= 6.9 Hz, 1H), 5.32 (s, 2H), 2.30 (s, 3H), 2.13 (s, 3H), 1.76 (d, J =7.2 Hz, 3H); ESI m/z 335 [M + H]+. 270 1-((1H-indol- 3-yl)methyl)-3-amino-5- (3,5- dimethyl- isoxazol-4- yl)pyridin- 2(1H)-one

P 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H),7.51 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.07 (t, J = 7.9 Hz,1H), 7.04 (d, J = 2.2 Hz, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.37 (d, J =2.2 Hz, 1H), 5.26 (s, 4H), 2.26 (s, 3H), 2.09 (s, 3H); ESI m/z 335 [M +H]+. 271 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-((3- methyl-1H-indol-4- yl)methyl) pyridin- 2(1H)-one

P 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H),7.12-7.95 (m, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H),6.50 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 5.58 (s, 2H), 5.28(s, 2H), 2.37 (d, J = 0.5 Hz, 3H), 2.22 (s, 3H), 2.05 (s, 3H); ESI m/z349 [M + H]+. 272 5-((3-amino- 5-(3,5- dimethyl- isoxazol-4- yl)-2-oxopyridin- 1(2H)- yl)methyl)- 2-bromo- benzonitrile

P 1H NMR (500 MHz, DMSO-d6): δ 7.95 (d, J = 2.0 Hz, 1H), 7.87 (d, J =8.5 Hz, 1H), 7.60-7.58 (m, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.45 (d, J =2.0 Hz, 1H), 5.31 (s, 2H), 5.13 (s, 2H), 2.36 (s, 3H), 2.18 (s, 3H); ESIm/z 399 [M + H]+. 273 4-((3-amino- 5-(3,5- dimethyl- isoxazol-4- yl)-2-oxopyridin- 1(2H)- yl)methyl)- 2-bromo- benzonitrile

P 1H NMR (500 MHz, DMSO-d6): δ 7.93 (d, J = 8.0 Hz, 1H), 7.84 (d, J =1.5 Hz, 1H), 7.48-7.46 (m, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.47 (d, J =2.5 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 2.36 (s, 3H), 2.19 (s, 3H); ESIm/z 399 [M + H]+. 274 3-amino-5- (3,5- dimethyl- isoxazol-4- yl)-1-(quinolin-5- ylmethyl) pyridin- 2(1H)-one

P 1H NMR (500 MHz, DMSO-d6) δ 8.95 (dd, J = 4.1, 1.4 Hz, 1H), 8.74 (d, J= 8.1 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.62(dd, J = 8.5, 4.2 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 2.2Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 5.66 (s, 2H), 5.36 (s, 2H), 2.28 (s,3H), 2.12 (s, 3H); ESI m/z 347 [M + H]+.

Example 1642-Benzyl-4-(2-hydroxy-3,4-dimethoxyphenyl)phthalazin-1(2H)-one

1,2,3-trimethoxybenzene (2.0 g, 11.9 mmol) was slowly added to asuspension of aluminum chloride (1.6 g, 11.9 mmol) in dichloromethane(50 mL) at 0° C. After the addition was complete phthalic anhydride(1.76 g, 11.9 mmol) was added. The resulting solution heated to refluxand stirred overnight. After that time, the reaction was cooled to rt,concentrated under reduced pressure and cautiously quenched withice-water. The resulting mixture was extracted with dichloromethane(3×100 mL). The organic phase was dried and concentrated under reducedpressure. The resulting material was combined with N-benzylhydrazinehydrochloride (0.68 g, 3.5 mmol) and potassium acetate (1.62 g, 16.5mmol) in ethanol (100 mL). The mixture was heated to reflux for 18 h.After that time, the reaction was cooled to rt, concentrated underreduced pressure and diluted with dichloromethane (200 mL). The organicphase was washed with saturated NaHCO₃, then water, dried over Na₂SO₄and concentrated under reduced pressure. The product was purified byflash column chromatography (silica gel, hexanes/ethyl acetate) to give2-benzyl-4-(2,3,4-trimethoxyphenyl)phthalazin-1(2H)-one (0.37 g, 28%) asa colorless solid: mp 144-145° C.; ¹H NMR (400 M Hz, CDCl₃) δ 8.49 (d,J=7.4 Hz, 1H), 7.76-7.66 (m, 2H), 7.49 (d, J=7.4 Hz, 2H), 7.41 (d, J=7.8Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.22 (m, 1H), 7.04 (d, J=8.6 Hz, 1H),6.80 (d, J=8.6 Hz, 1H), 5.47 (s, 2H), 3.94 (s, 6H), 3.64 (s, 3H); ESI MSm/z 389.1 [M+H]⁺.

Example 165 2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)-2H-phthalazin-1-one

Sodium hydride (60% suspension in mineral oil, 0.92 g, 22.8 mmol) wasadded in one portion to a stirred suspension of4-chloro-2H-phthalazin-1-one (3.74 g, 20.7 mmol) in anhydrous DMF (80mL). The reaction was stirred for 15 min and then cooled to 10° C.Benzyl bromide (4.25 g, 24.8 mmol) was added drop wise and the reactionmixture was then stirred for 21 h at rt. After that time the reactionwas diluted with ethyl acetate (200 mL), washed with water (5×80 mL)then brine (80 mL), dried over MgSO₄ and concentrated under reducedpressure. The resulting pale yellow solid was suspended in hexanes (80mL) and stirred for 3 h. After that time, the precipitate was collectedby filtration, washed with hexanes and dried to give2-benzyl-4-chloro-2H-phthalazin-1-one (5.05 g, 90%) as white solid: ¹HNMR (400 MHz, CDCl₃) δ 8.45 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H),7.97-7.83 (m, 2H), 7.50 (d, J=6.8 Hz, 2H), 7.36-7.7.29 (m, 3H), 5.37 (s,2H).

A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol),2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenol (1.50g, 6 mmol), Pd(PPh₃)₄ (0.87 g, 0.75 mmol) and Na₂CO₃ (2.12 g, 20 mmol)in toluene (25 mL), ethanol (12.5 mL) and water (12.5 mL) was degassedand then heated to reflux with stirring for 19 h. After that time, thereaction was cooled to rt and diluted with ethyl acetate (150 mL) andwater (100 mL). The organic phase was separated, washed with water (2×30mL) then brine (50 mL), dried over MgSO₄ and concentrated under reducedpressure. The residue was triturated with hexanes (100 mL) to give ayellow solid. The product was purified by flash column chromatography(silica gel, 70:30 hexanes/ethyl acetate) followed by recrystallizationfrom CHCl₃/hexanes to give2-benzyl-4-(4-hydroxy-3-methoxyphenyl)phthalazin-1(2H)-one (0.135 g,7.5%) as a white solid: mp 197-200° C.; ¹H NMR (400 MHz, CDCl₃) δ8.54-8.52 (m, 1H), 7.79-7.71 (m, 3H), 7.52 (d, J=7.2 Hz, 2H), 7.34-7.25(m, 4H), 7.11-7.04 (m, 2H), 5.82 (s, 1H), 5.47 (s, 2H), 3.93 (s, 3H);ESI MS m/z 359 [M+1]⁺.

Example 166 2-Benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one

A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.377 g, 1.20 mmol),2-(3,4-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3-dioxolane (0.380 g, 1.44mmol) and Na₂CO₃ (0.382 g, 3.60 mmol) was degassed under nitrogen.Toluene (20 mL), ethanol (20 mL) and water (2 mL) were then added. Thereaction mixture was degassed again and Pd(PPh₃)₄ (0.139 g, 0.12 mmol)was added. The reaction was stirred at 90° C. for 16 h under nitrogen.After that time, the mixture was cooled to rt and concentrated underreduced pressure. The residue was diluted with water (50 mL) andextracted with ethyl acetate (2×100 mL). The organic phase was washedwith water, brine, dried over Na₂SO₄ and concentrated under reducedpressure. The product was purified by flash column chromatography(silica gel, 70:30 hexanes/ethyl acetate to 60:40 hexanes/ethyl acetate)to give 2-benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one (0.385 g,86%) as a pale yellow solid: mp 174-176° C.; ¹H NMR (400 MHz, CDCl₃): δ8.57 (d, J=7.81 Hz, 1H), 7.47-7.66 (m, 3H), 7.24-7.42 (m, 5H), 7.06 (s,1H), 6.85-6.98 (m, 3H), 5.27 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H). ESI MSm/z 372 [M+H]⁺.

Example 167 2-Benzyl-4-(3,5-dimethylisoxazol-4-yl) isoquinolin-1(2H)-one

Sodium hydride (60% dispersion in mineral oil, 0.656 g, 16.4 mmol) wascarefully added to a solution of 4-bromoisoquinolin-1(2H)-one (3.5 g,15.6 mmol) in anhydrous DMF (60 mL) cooled to 0° C. The reaction wasstirred at 0° C. for 30 min, then benzyl bromide (8.02 g, 46.9 mmol) wasadded slowly. The reaction was allowed to warm to rt and stirred for 17h. After that time the reaction was diluted with water (200 mL) andextracted with ethyl acetate (3×200 mL). The organic phase was washedwith water, brine, dried over Na₂SO₄ and concentrated under reducedpressure. The product was purified by flash column chromatography(silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate)to give 2-benzyl-4-bromoisoquinolin-1(2H)-one (4.55 g, 93%) as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=7.4 Hz, 1H), 7.79-7.84 (m,1H), 7.71-7.79 (m, 1H), 7.53-7.60 (m, 1H), 7.29-7.38 (m, 6H), 5.21 (s,2H); ESI MS m/z 314 [M+H]⁺ and 316 [M+H]⁺.

A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.320 g, 1.02 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(0.341 g, 1.53 mmol) and Na₂CO₃ (0.324 g, 3.06 mmol) in toluene (20 mL),ethanol (10 mL) and water (3 mL) was degassed under nitrogen. Pd(PPh₃)₄(0.118 g, 0.10 mmol) was then added and the reaction was stirred at 100°C. for 17 h under nitrogen. After that time, the mixture was cooled tort and concentrated under reduced pressure. The residue was dissolved inethyl acetate (100 mL) and washed with water, brine, dried over Na₂SO₄and concentrated under reduced pressure. The product was purified byflash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to75:25 hexanes/ethyl acetate) to give2-benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one (0.140 g,42%) as an off white solid: mp 139-141° C.; ¹H NMR (400 MHz, CDCl₃) δ8.56 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.51-7.60 (m, 1H), 7.29-7.39(m, 5H), 7.19 (d, J=7.8 Hz, 1H), 6.97 (s, 1H), 5.18-5.33 (m, 2H), 2.23(s, 3H), 2.06 (s, 3H); ESI MS m/z 331 [M+H]⁺.

Example 168 2-Benzyl-4-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one

A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.420 g, 1.34 mmol),4,4,5,5-tetramethyl-2-(3,4,5-trimethoxyphenyl)-1,3,2-dioxaborolane(0.511 g, 1.74 mmol) and Na₂CO₃ (0.425 g, 4.01 mmol) in toluene (20 mL),ethanol (10 mL) and water (3 mL) was degassed under nitrogen. Pd(PPh₃)₄(0.154 g, 0.13 mmol) was then added and the reaction mixture was stirredat 100° C. for 17 h under nitrogen. After that time, the mixture wascooled to rt and concentrated under reduced pressure. The residue wasdissolved in ethyl acetate (100 mL) and washed with water, brine, driedover Na₂SO₄ and concentrated under reduced pressure. The product waspurified by flash column chromatography (silica gel, 90:10 hexanes/ethylacetate to 75:25 hexanes/ethyl acetate) to give2-benzyl-4-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one (0.298 g, 55%)as an off white solid: mp 166-168° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.57(d, J=7.8 Hz, 1H), 7.49-7.66 (m, 3H), 7.28-7.41 (m, 5H), 7.08 (s, 1H),6.57 (s, 2H), 5.28 (s, 2H), 3.91 (s, 3H), 3.85 (s, 6H); ESI MS m/z 402[M+H]⁺.

Example 169 2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)isoquinolin-1(2H)-one

A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.50 g, 1.59 mmol),2-methoxy-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenol (0.477 g, 1.90mmol) and Na₂CO₃ (0.843 g, 7.95 mmol) in toluene (30 mL), ethanol (30mL) and water (5 mL) was degassed under nitrogen. Pd(PPh₃)₄ (0.183 g,0.157 mmol) was added and the reaction was stirred at 90° C. for 16 hunder nitrogen. After that time, the mixture was cooled to rt anddiluted with ethyl acetate (250 mL). The organic phase was separated,washed with water and brine, dried over Na₂SO₄ and concentrated underreduced pressure. The product was purified by flash columnchromatography (silica gel, 70:30 hexanes/ethyl acetate) to give2-benzyl-4-(4-hydroxy-3-methoxyphenyl) isoquinolin-1(2H)-one (0.253 g,45%) as a white solid: mp 165-167° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.56(d, J=8.2 Hz, 1H), 7.58-7.65 (m, 1H), 7.50-7.57 (m, 2H), 7.28-7.40 (m,5H), 7.05 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.84-6.89 (m, 2H), 5.70 (s,1H), 5.27 (s, 2H), 3.89 (s, 3H); ESI MS m/z 358 [M+H]⁺.

Example 170 2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2H-phthalazin-1-one

A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)isoxazole(1.34 g, 6 mmol), Pd(PPh₃)₄ (0.58 g, 0.5 mmol) and Na₂CO₃ (1.59 g, 15mmol) in toluene (25 mL), ethanol (12.5 mL) and water (12.5 mL) wasdegassed and heated to reflux with stirring for 18 h. After that time,the mixture was cooled to rt and diluted with ethyl acetate (80 mL). Theorganic phase was separated, washed with water and brine, dried overMgSO₄ and concentrated under reduced pressure. The resulting semi-solidwas triturated with hexanes to give a yellow solid. The product waspurified by flash column chromatography (silica gel, 80:20 hexanes/ethylacetate) followed by recrystallization from CHCl₃/hexanes to give2-benzyl-4-(3,5-dimethylisoxazol-4-yl)phthalazin-1(2H)-one (0.39 g, 23%)as a white solid: mp 186-188° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.53(m, 1H), 7.83-7.76 (m, 2H), 7.48 (d, J=7.2 Hz, 2H), 7.44-7.42 (m, 1H),7.35-7.26 (m, 3H), 5.45 (s, 2H), 2.31 (s, 3H), 2.15 (s, 3H).

Example 171 2-Benzyl-4-(3,4,5-trimethoxyphenylamino)-2H-phthalazin-1-one

A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol),3,4,5-trimethoxyaniline (1.10 g, 6 mmol),bis(dibenzylideneacetone)palladium(II) (0.46 g, 0.5 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (0.62 g, 1 mmol) andpotassium tert-butoxide (0.84 g, 7.5 mmol) in anhydrous toluene (20 mL)was degassed and heated to reflux with stirring for 19 h. After thattime, the mixture was cooled to rt and quenched with saturated aqueousNH₄Cl (20 mL). Ethyl acetate (20 mL) and water (20 mL) were added andthe organic phase was separated, washed with brine (20 mL), dried overMgSO₄ and concentrated under reduced pressure. The product was purifiedby flash column chromatography (silica gel, 60:40 hexanes/ethyl acetate)followed by recrystallization from CHCl₃/hexanes to give2-benzyl-4-((3,4,5-trimethoxyphenyl)amino)phthalazin-1(2H)-one (0.598 g,29%) as a white solid: mp 206-207° C.; ¹H H NMR (400 MHz, CDCl₃) δ8.57-8.55 (m, 1H), 7.84-7.76 (m, 3H), 7.41 (d, J=6.8 Hz, 2H), 7.32-7.22(m, 3H), 6.69 (s, 2H), 6.40 (s, 1H), 5.38 (s, 2H), 3.81 (s, 3H), 3.70(s, 6H); ESI MS m/z 418 [M+1]⁺.

Example 1722-Benzyl-4-((3,4,5-trimethoxyphenyl)amino)isoquinolin-1(2H)-one

A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.500 g, 1.59 mmol)and 3,4,5-trimethoxyaniline (0.349 g, 1.91 mmol) in dry toluene (30 mL)was degassed under nitrogen. Pd₂(dba)₃ (0.218 g, 0.24 mmol) and BINAP(0.297 g, 0.48 mmol) were added and the mixture was degassed again.Sodium tert-butoxide (0.306 g, 3.18 mmol) was then added and thereaction was stirred at 100° C. for 17 h under nitrogen. After thattime, the reaction mixture was cooled to rt, diluted with water (20 mL)and extracted with ethyl acetate (3×20 mL). The organic phase was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.The product was purified by flash column chromatography (silica gel,25:75 hexanes/ethyl acetate to 50:50 hexanes/ethyl acetate) followed bytrituration with methanol to give2-benzyl-4-((3,4,5-trimethoxyphenyl)amino)isoquinolin-1(2H)-one (0.183g, 28%) as a light brown solid: mp 162-164° C.; ¹H NMR (400 MHz, CDCl₃)δ 8.53 (d, J=8.2 Hz, 1H), 7.61-7.68 (m, 2H), 7.54 (ddd, J=8.2, 5.6, 2.7Hz, 1H), 7.27-7.35 (m, 5H), 7.17 (s, 1H), 5.85 (s, 2H), 5.23 (s, 2H),5.10 (s, 1H), 3.75 (s, 3H), 3.65 (s, 6H); ESI MS m/z 417 [M+H]⁺.

Example 1736-Benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one

To a solution of 8-bromo-1,6-naphthyridin-5(6H)-one (0.225 g, 1.0 mmol)in anhydrous DMF (6 mL) was added sodium hydride (60% dispersion inmineral oil, 0.052 g, 1.3 mmol) at 0° C. The resulting mixture wasstirred at 0° C. for 45 min and then benzyl bromide (0.205 g, 1.2 mmol)was added slowly. The reaction mixture was stirred at 0° C. for 2 h,then allowed to warm to rt and stirred for 17 h. After that time,saturated NH₄Cl solution (5 mL) and water (5 mL) were added and themixture was extracted with ethyl acetate (2×25 mL). The organic phasewas washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The product was purified by flash columnchromatography (silica gel, 99:1 dichloromethane/methanol to 97:3dichloromethane/methanol) to give6-benzyl-8-bromo-1,6-naphthyridin-5(6H)-one (0.270 g, 86%) as anoff-white solid: ¹H NMR (400 MHz, CDCl₃) δ 9.04 (dd, J=4.5, 1.8 Hz, 1H),8.71-8.77 (m, 1H), 7.65 (s, 1H), 7.50 (dd, J=8.0, 4.5 Hz, 1H), 7.30-7.41(m, 5H), 5.22 (s, 2H); ESI MS m/z 315 [M+H]⁺ and 317 [M+H]⁺.

A mixture of 6-benzyl-8-bromo-1,6-naphthyridin-5(6H)-one (0.260 g, 0.82mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.174 g, 1.24 mmol) andNa₂CO₃ (0.262 g, 2.47 mmol) in toluene (25 mL), ethanol (15 mL) andwater (5 mL) was degassed. Pd(PPh₃)₄ (0.095 g, 0.08 mmol) was then addedand the reaction heated at 95° C. for 17 h. After that time the reactionwas cooled to rt and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (100 mL), washed with water and brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theproduct was purified by flash column chromatography (silica gel, 99:1ethyl acetate/methanol) to give6-benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one (0.180g, 66%) as a white solid: mp 192-195° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.92(dd, J=4.5, 1.9 Hz, 1H), 8.78 (dd, J=8.0, 1.9 Hz, 1H), 7.47 (dd, J=8.0,4.5 Hz, 1H), 7.30-7.41 (m, 5H), 7.20 (s, 1H), 5.27 (s, 2H), 2.25 (s,3H), 2.11 (s, 3H); ESI MS m/z 332 [M+H]⁺.

Example 1747-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one

To a suspension of 5-bromo-1,7-naphthyridin-8(7H)-one (0.50 g, 2.22mmol) in anhydrous DMF (60 mL) was added benzyl bromide (0.34 mL, 2.88mmol) and Cs₂CO₃ (0.94 g, 2.88 mmol). The reaction was stirred at rt for16 h. After that time the reaction was concentrated under reducedpressure, diluted with water (50 mL) and extracted with ethyl acetate(100 mL). The organic phase was washed with water then brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The productwas purified by flash column chromatography (silica gel, 98:2dichloromethane/methanol) to give7-benzyl-5-bromo-1,7-naphthyridin-8(7H)-one (0.584 g, 83%) as a brownsolid: ¹H NMR (400 MHz, CDCl₃) δ 8.93 (dd, J=4.4, 1.5 Hz, 1H), 8.16 (dd,J=8.2, 1.5 Hz, 1H), 7.66 (dd, J=8.2, 4.4 Hz, 1H), 7.42 (s, 1H),7.28-7.41 (m, 5H), 5.28 (s, 2H); ESI MS m/z 314.9 [M+H]⁺ and 316.9[M+H]⁺.

A mixture of 7-benzyl-5-bromo-1,7-naphthyridin-8(7H)-one (0.574 g, 1.82mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.385 g, 2.73 mmol) andNa₂CO₃ (0.579 g, 5.46 mmol) was degassed under nitrogen. Then toluene(30 mL), ethanol (30 mL) and water (3 mL) were added. The reactionmixture was degassed again and Pd(PPh₃)₄ (0.210 g, 0.12 mmol) was addedand degassing procedure was repeated. The reaction was stirred at 90° C.for 6 h under nitrogen. After that time the reaction was cooled to rt,concentrated under reduced pressure, diluted with water (50 mL) andextracted with ethyl acetate (2×100 mL). The organic phase was washedwith water then brine, dried over Na₂SO₄, and concentrated under reducedpressure. The product was purified by flash column chromatography(silica gel, dichloromethane to 97:3 dichloromethane/methanol) to give7-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one (0.341g, 56%) as a tan solid: mp 168-170° C.; ¹H NMR (400 MHz, CDCl₃): δ8.92-9.00 (m, 1H), 7.52-7.60 (m, 2H), 7.29-7.42 (m, 5H), 7.04 (s, 1H),5.26-5.43 (m, 2H), 2.22 (s, 3H), 2.04 (s, 3H); ESI MS m/z 332.0 [M+H]⁺.

Example 1752-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one

To a solution of 4-iodo-2,7-naphthyridin-1(2H)-one (0.544 g, 2.0 mmol)in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion inmineral oil, 0.104 g, 2.6 mmol) at 0° C. The resulting mixture wasstirred at 0° C. for 30 min and then benzyl bromide (0.410 g, 2.4 mmol)was added slowly. The reaction was stirred at 0° C. for 2 h, thenallowed to warm to rt and stirred for 17 h. Saturated NH₄Cl solution (5mL) and water (5 mL) were added and the mixture was extracted with ethylacetate (2×25 mL). The organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The productwas purified by flash column chromatography (silica gel, 99:1dichloromethane/methanol to 97:3 dichloromethane/methanol) to give2-benzyl-4-iodo-2,7-naphthyridin-1(2H)-one (0.540 g, 75%) as anoff-white solid: ¹H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.84 (d, J=5.5Hz, 1H), 7.68 (s, 1H), 7.45 (d, J=5.5 Hz, 1H), 7.30-7.41 (m, 5H), 5.19(s, 2H); ESI MS m/z 363 [M+H]⁺.

A mixture of 2-benzyl-4-iodo-2,7-naphthyridin-1(2H)-one (0.540 g, 1.49mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.315 g, 2.24 mmol) andNa₂SO₄ (0.474 g, 4.47 mmol) in toluene (25 mL), ethanol (25 mL) andwater (4 mL) was degassed. Pd(PPh₃)₄ (0.172 g, 0.15 mmol) was then addedand the reaction mixture was heated at 95° C. for 6 h. After that timethe reaction was cooled to rt, concentrated under reduced pressure anddiluted with ethyl acetate (100 mL). The organic phase was washed withwater then brine, dried over Na₂SO₄, and concentrated under reducedpressure. The product was purified by flash column chromatography(silica gel, dichloromethane to 99:1 ethyl acetate/methanol) to give2-benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one (0.260g, 54%) as an off-white solid: mp 174-177° C.; ¹H NMR (400 MHz, CDCl₃) δ9.73 (s, 1H), 8.75 (d, J=5.4 Hz, 1H), 7.31-7.41 (m, 5H), 7.16 (s, 1H),7.02 (d, J=5.4 Hz, 1H), 5.26 (s, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MSm/z 332 [M+H]⁺.

Example 1762-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one

Benzyl bromide (0.057 g, 0.34 mmol) was added to a mixture of4-iodo-2,6-naphthyridin-1(2H)-one trifluororoacetate (0.100 g, 0.26mmol) and Cs₂CO₃ (0.253 g, 0.78 mmol) in anhydrous DMF (10 mL) cooled to0° C. The reaction was stirred at 0° C. for 30 min, then allowed to warmto rt and stirred for 17 h. After that time the reaction wasconcentrated under reduced pressure, diluted with water (10 mL), andextracted with ethyl acetate (2×25 mL). The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The product was purified by flash column chromatography(silica gel, 99:1 dichloromethane/methanol to 97:3dichloromethane/methanol) to give2-benzyl-4-iodo-2,6-naphthyridin-1(2H)-one (0.070 g, 74%) as anoff-white solid: ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 8.78 (d, J=5.3Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.31-7.40 (m, 5H), 5.20(s, 2H); ESI MS m/z 363 [M+H]⁺.

A mixture of 2-benzyl-4-iodo-2,6-naphthyridin-1(2H)-one (0.070 g, 0.19mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.041 g, 0.29 mmol) andNa₂CO₃ (0.062 g, 0.58 mmol) in toluene (15 mL), ethanol (15 mL) andwater (2 mL) was degassed. Pd(PPh₃)₄ (0.022 g, 0.19 μmol) was then addedand the reaction was heated at 95° C. for 17 h. After that time thereaction was cooled to rt, concentrated under reduced pressure anddiluted with ethyl acetate (30 mL). The organic phase was washed withwater then brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The product was purified by flash columnchromatography (silica gel, 99:1 dichloromethane/methanol) followed bytrituration with diethyl ether to give2-benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one (0.020g, 32%) as an off-white solid: mp 159-161° C.; ¹H NMR (400 MHz, CDCl₃) δ8.78 (d, J=5.4 Hz, 1H), 8.65 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 7.30-7.40(m, 5H), 7.04 (s, 1H), 5.26 (s, 2H), 2.26 (s, 3H), 2.09 (s, 3H); ESI MSm/z 332 [M+H]⁺.

Example 177 2-Benzyl-4-(2,3,4-trimethoxyphenyl)phthalazin-1(2H)-one

Example 177 was isolated as a byproduct from the procedure described forExample 164. Continued elution during the purification process provided2-benzyl-4-(2-hydroxy-3,4-dimethoxyphenyl)phthalazin-1(2H)-one (0.37 g,28%) as a colorless solid: mp 155-156° C.; ¹H NMR (400 M Hz, CDCl₃) δ8.51 (d, J=7.5 Hz, 1H), 7.79-7.69 (m, 2H), 7.63 (d, J=7.5 Hz, 2H), 7.51(d, J=7.6 Hz, 2H), 7.36-7.30 (m, 1H), 7.30-7.24 (m, 1H), 7.10 (d, J=8.6Hz, 1H), 6.74 (s, 1H), 6.63 (d, J=8.6 Hz, 1H), 5.47 (s, 2H), 3.97 (s,3H), 3.94 (s, 3H); ESI MS m/z 389 [M+H]⁺.

Example 275 Inhibition of Tetra-Acetylated Histone H4 Binding IndividualBET Bromodomains

Proteins were cloned and overexpressed with a N-terminal 6×His tag, thenpurified by nickel affinity followed by size exclusion chromatography.Briefly, E. coli BL21 (DE3) cells were transformed with a recombinantexpression vector encoding N-terminally Nickel affinity taggedbromodomains from Brd2, Brd3, Brd4. Cell cultures were incubated at 37°C. with shaking to the appropriate density and induced overnight withIPTG. The supernatant of lysed cells was loaded onto Ni-IDA column forpurification. Eluted protein is pooled, concentrated and furtherpurified by size exclusion chromatography. Fractions representingmonomeric protein were pooled, concentrated, aliquoted, and frozen at−80° C. for use in subsequent experiments.

Binding of tetra-acetylated histone H4 and BET bromodomains wasconfirmed by a Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET) method. N-terminally His-tagged bromodomains (200 nM) andbiotinylated tetra-acetylated histone H4 peptide (25-50 nM, Millipore)were incubated in the presence of Europium Cryptate-labeled streptavidin(Cisbio Cat. #610SAKLB) and XL665-labeled monoclonal anti-His antibody(Cisbio Cat. #61HISXLB) in a white 96 well microtiter plate (Greiner).For inhibition assays, serially diluted test compound was added to thesereactions in a 0.2% final concentration of DMSO. Final bufferconcentrations were 30 mM HEPES pH 7.4, 30 mM NaCl, 0.3 mM CHAPS, 20 mMphosphate pH 7.0, 320 mM KF, 0.08% BSA). After a 2-h incubation at roomtemperature, the fluorescence by FRET was measured at 665 and 620 nm bya SynergyH4 plate reader (Biotek). Illustrative results with the firstbromodomain of Brd4 and the second bromodomain of Brd2 are shown below.The binding inhibitory activity was shown by a decrease in 665 nmfluorescence relative to 620 nm. IC₅₀ values were determined from a doseresponse curve.

Compounds with an IC₅₀ value less than 30 μM were deemed to be active.

TABLE 2 Inhibition of Tetra-acetylated Histone H4 Binding to Brd4bromodomain 1 (BRD4(1) and Brd 3 bromodomain 2 (BRD2(2) as Measured byFRET FRET activity FRET activity FRET activity Example (IC50 <30 μM)Example (IC50 <30 μM) Example (IC50 <30 μM) Number BRD2(2)-BRD4(1)Number BRD2(2)-BRD4(1) Number BRD2(2)-BRD4(1) 1 Active Active 2 ActiveActive 3 Active Not Active 4 Active Active 5 Active Active 6 ActiveActive 7 Active Active 8 Active Active 9 Active Active 10 Active Active11 Active Active 12 Active Active 13 Active Active 14 Active Active 15Active Active 16 Active Active 17 Active Active 18 Active Active 19Active Active 20 Active Not Active 21 Active Active 22 Active Active 23Active Active 24 Active Active 25 Active Active 26 Active Active 27Active Active 28 Active Active 29 Active Active 30 Active Active 31Active Active 32 Active Not Active 33 Active Active 34 Active Active 35Active Active 36 Active Active 37 Active Active 38 Active Active 39Active Active 40 Active Active 41 Active Active 42 Active Active 43Active Active 44 Active Active 45 Active Active 46 Active Active 47Active Active 48 Active Active 49 Active Active 50 Active Active 51Active Active 52 Active Active 53 Active Active 54 Active Active 55Active Active 56 Active Active 57 Active Active 58 Active Not Active 59Active Not Active 60 Active Active 61 Active Active 62 Active Not Active63 Active Active 64 Active Active 65 Active Active 66 Active Active 67Active Active 68 Active Active 69 Active Active 70 Active Active 71Active Active 72 Active Active 73 Active Active 74 Active Active 75Active Active 76 Active Active 77 Active Active 78 Active Active 79Active Active 80 Active Not Active 81 Active Not Active 82 Active Active83 Active Active 84 Active Active 85 Active Active 86 Active Active 87Active Active 88 Active Active 89 Active Active 90 Active Active 91Active Active 92 Active Active 93 Active Active 94 Active Active 95Active Active 96 Active Active 97 Not Active Active 98 Active Active 99Active Active 100 Active Not Active 101 Active Active 102 Active Active103 Active Active 104 Active Active 105 Active Active 106 Active Active107 Active Active 108 Active Active 109 Active Active 110 Active Active111 Active Active 112 Active Active 113 Active Active 114 Active Active115 Active Active 116 Active Active 117 Active Active 118 Active Active119 Active Active 120 Active Active 121 Active Active 122 Active Active123 Active Active 124 Active Active 125 Active Active 126 Active Active127 Active Active 128 Active Active 129 Active Active 130 Active Active131 Active Active 132 Active Active 133 Active Active 134 Active Active135 Active Active 136 Active Active 137 Active Active 138 Active Active139 Active Active 140 Active Active 141 Active Active 142 Active Active143 Active Active 144 Active Active 145 Active Active 146 Active Active147 Active Active 148 Active Active 149 Active Active 150 Not ActiveActive 151 Active Active 152 Not Tested Active 153 Not Tested Active 154Not Tested Active 155 Not Tested Active 156 Not Tested Active 157 NotTested Active 158 Not Tested Active 159 Not Tested Active 160 Not TestedActive 161 Not Tested Not Active 162 Active Active 163 Active Active 164Active Active 165 Active Active 166 Not Active Active 167 Active Active168 Active Not Active 169 Active Active 170 Active Not Active 171 ActiveActive 172 Active Active 173 Active Active 174 Active Active 175 ActiveActive 176 Active Active 177 Active Active 178 Not Tested Active 179 NotTested Active 180 Not Tested Active 181 Not Tested Active 182 Not TestedActive 183 Not Tested Active 184 Not Tested Active 185 Not Tested Active186 Not Tested Active 187 Not Tested Active 188 Not Tested Active 189Not Tested Active 190 Not Tested Active 191 Not Tested Active 192 NotTested Active 193 Not Tested Not Active 194 Not Tested Active 195 NotTested Active 196 Not Tested Active 197 Not Tested Not Active 198 NotTested Active 199 Not Tested Not Active 200 Not Tested Not Active 201Not Tested Not Active 202 Not Tested Active 203 Not Tested Active 204Not Tested Active 205 Not Tested Active 206 Not Tested Active 207 NotTested Active 208 Not Tested Active 209 Not Tested Active 210 Not TestedActive 211 Not Tested Active 212 Not Tested Active 213 Not Tested Active214 Not Tested Active 214 Not Tested Active 215 Not Tested Active 216Not Tested Active 217 Not Tested Active 218 Not Tested Active 219 NotTested Active 220 Not Tested Active 221 Not Tested Active 222 Not TestedActive 223 Not Tested Active 224 Not Tested Active 225 Not Tested NotActive 226 Not Tested Active 227 Not Tested Active 228 Not Tested Active229 Not Tested Active 230 Not Tested Active 231 Not Tested Active 232Not Tested Active 233 Not Tested Active 234 Not Tested Active 235 NotTested Active 236 Not Tested Active 237 Not Tested Active 238 Not TestedActive 239 Not Tested Active 240 Not Tested Active 241 Not Tested Active242 Not Tested Active 243 Not Tested Active 244 Not Tested Active 245Not Tested Active 246 Not Tested Active 247 Not Tested Active 248 NotTested Active 249 Not Tested Not Active 250 Not Tested Active 251 NotTested Active 252 Not Tested Active 253 Not Tested Active 254 Not TestedActive 255 Not Tested Active 256 Not Tested Active 257 Not Tested Active258 Not Tested Active 259 Not Tested Not Active 260 Not Tested NotActive 261 Not Tested Active 262 Not Tested Active 263 Not Tested Active264 Not Tested Active 265 Not Tested Not Active 266 Not Tested NotActive 267 Not Tested Active 268 Not Tested Not Active 269 Not TestedNot Active 270 Not Tested Active 271 Not Tested Active 272 Not TestedActive 273 Not Tested Active 274 Not Tested Active — — —

Example 276 Inhibition of c-Myc Expression in Cancer Cell Lines

MV4-11 cells (2.5×10⁴ cells) were plated in 96 well U-bottom plates withtest compound or DMSO (0.1%), and incubated for 3 h at 37° C. Cells werethen harvested by centrifugation, lysed, and mRNA was isolated using themRNA catcher plus kit (Invitrogen). Reverse transcription of the mRNAand duplex amplification of the c-myc and cyclophilin cDNAs wasperformed using the RNA Ultrasense kit (Invitrogen) and a ViiA7real-time PCR machine (Applied Biosystems). IC₅₀ values were determinedfrom a dose response curve.

Compounds with an IC₅₀ value less than 30 μM were deemed to be active.

TABLE 3 Inhibition of c-myc Activity in Human AML MV4-11 cells c-mycc-myc c-myc c-myc Example activity Example activity Example activityExample activity Number (IC50 <30 μM) Number (IC50 <30 μM) Number (IC50<30 μM) Number (IC50 <30 μM) 1 Not Active 2 Not Active 4 Active 5 Active13 Not Active 14 Not Active 15 Not Active 16 Not Active 17 Active 19Active 21 Active 22 Not Active 24 Not Active 25 Active 28 Active 29Active 30 Not Active 34 Active 42 Active 43 Active 47 Active 49 Active50 Active 51 Not Active 52 Not Active 53 Not Active 54 Active 55 Active56 Active 60 Not Active 63 Active 64 Active 65 Active 66 Active 70Active 71 Active 72 Active 73 Active 75 Active 78 Active 79 Active 82Not Active 83 Not Active 84 Not Active 90 Not Active 91 Not Active 93Not Active 94 Not Active 95 Not Active 96 Active 98 Not Active 99 Active101 Active 104 Active 105 Active 107 Not Active 108 Active 109 Active113 Active 117 Not Active 118 Not Active 119 Not Active 120 Not Active121 Active 122 Active 123 Active 124 Active 125 Active 126 Active 127Active 128 Active 132 Active 133 Active 134 Active 135 Active 136 Active137 Active 142 Active 146 Active 147 Active 148 Active 149 Active 151Not Active 162 Active 164 Not Active 165 Active 167 Not Active 168 NotActive 169 Active 171 Active 172 Not Active 179 Active 180 Active 181Active 182 Active 183 Active 184 Active 185 Active 186 Active 187 NotActive 188 Not Active 189 Active 190 Active 191 Active 192 Active 193Not Active 194 Active 198 Not Active 203 Active 205 Active 206 Active207 Active 208 Active 209 Active 210 Active 211 Active 212 Active 213Active 215 Active 216 Active 219 Active 220 Active 222 Active 223 Active226 Active 227 Active 228 Active 230 Active 231 Active 233 Active 237Active 238 Active 240 Active 241 Active 242 Active 247 Active 251 Active252 Active 254 Active 255 Active 256 Active 261 Active 262 Active 263Active 264 Active 267 Active 270 Active 271 Active 272 Active 273 Active274 Active — —

Example 277 Inhibition of Cell Proliferation in Cancer Cell Lines

MV4-11 cells: 96-well plates were seeded with 5×10⁴ cells per well ofexponentially growing human AML MV-4-11 (CRL-9591) cells and immediatelytreated with two-fold dilutions of test compounds, ranging from 30 μM to0.2 μM. Triplicate wells were used for each concentration, as well as amedia only and three DMSO control wells. The cells and compounds wereincubated at 37° C., 5% CO₂ for 72 h before adding 20 μL of theCellTiter Aqueous One Solution (Promega) to each well and incubating at37° C., 5% CO₂ for an additional 3-4 h. The absorbance was taken at 490nm in a spectrophotometer and the percentage of proliferation relativeto DMSO-treated cells was calculated after correction from the blankwell. IC₅₀ were calculated using the GraphPad Prism software.

Compounds with an IC₅₀ value less than 30 μM were deemed to be active.

TABLE 4 Inhibition of Cell Proliferation in Human AML MV-4-11 cells CellCell Cell Cell Proliferation Proliferation Proliferation ProliferationExample activity Example activity Example activity Example activityNumber (IC50 <30 μM) Number (IC50 <30 μM) Number (IC50 <30 μM) Number(IC50 <30 μM) 1 Not Active 2 Not Active 4 Active 5 Active 6 Active 7Active 13 Not Active 14 Active 15 Not Active 17 Not Active 19 Active 21Not Active 22 Not Active 24 Active 25 Active 26 Active 27 Active 28Active 29 Active 30 Active 34 Active 42 Active 43 Active 47 Active 49Active 50 Active 51 Not Active 52 Not Active 53 Active 54 Active 55Active 56 Active 60 Not Active 63 Active 64 Active 65 Active 66 Active70 Active 73 Active 75 Active 78 Active 82 Not Active 83 Active 84 NotActive 87 Not Active 90 Not Active 91 Active 93 Active 94 Active 95 NotActive 96 Active 98 Active 99 Not Active 101 Active 104 Active 105Active 107 Active 108 Active 109 Active 113 Active 117 Not Active 118Active 119 Active 120 Active 122 Active 123 Active 124 Active 125 Active126 Active 127 Active 128 Active 132 Active 133 Not Active 134 Active136 Active 137 Active 142 Active 146 Not Active 147 Active 148 Active149 Active 151 Active 162 Active 164 Active 165 Active 167 Active 168Active 169 Active 171 Active 172 Active 179 Active 180 Active 181 NotActive 182 Not Active 183 Active 184 Active 185 Active 186 Active 187Not Active 188 Not Active 189 Active 190 Active 191 Active 192 Active193 Active 194 Active 198 Not Active 203 Active 205 Active 206 Active207 Active 208 Active 209 Active 210 Active 211 Active 212 Active 213Active 215 Active 216 Active 219 Active 220 Active 222 Active 223 Active226 Active 227 Active 228 Active 230 Active 231 Active 233 Active 237Active 238 Active 240 Active 241 Active 242 Active 246 Active 247 Active250 Active 251 Active 252 Active 254 Active 255 Active 256 Active 261Active 262 Active 263 Active 264 Active 267 Active 270 Active 271 Active272 Active 273 Active 274 Active

Example 278 Inhibition of hIL-6 mRNA Transcription

In this example, hIL-6 mRNA in tissue culture cells was quantitated tomeasure the transcriptional inhibition of hIL-6 when treated with acompound of the present disclosure.

A human leukemic monocyte lymphoma cell line (U937) was plated (3.2×10⁴cells per well) in a 96-well plate in 1004 RPMI-1640 containing 10% FBSand penicillin/streptomycin, and differentiated into macrophages for 3days in 60 ng/mL PMA (phorbol-13-myristate-12-acetate) at 37° C. in 5%CO₂ prior to the addition of the compound of interest. The cells werepretreated for 1 h with the test compound prior to stimulation with 1ug/mL lipopolysaccharide from Escherichia coli. The cells were incubatedat 37° C. for 3 h before the cells were harvested. At time of harvest,the spent media was removed from the cells and the cells were rinsed in2004 PBS. Cell lysis solution (70 μL) was added the cells in each welland incubated for 5-10 min at room temperature, to allow for completecell lysis and detachment. mRNA was then prepared using the “mRNACatcher PLUS plate” (Invitrogen), according to the protocol supplied.After the last wash, as much wash buffer as possible was aspiratedwithout allowing the wells to dry. Elution buffer (E3, 70 μL) was thenadded to each well. mRNA was then eluted by incubating the mRNA CatcherPLUS plate with Elution Buffer for 5 min at 68° C. and then immediatelyplacing the plate on ice.

The eluted mRNA isolated was then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data wasanalyzed, normalizing the Ct values for hIL-6 to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

Compounds with an IC₅₀ value less than 30 μM were deemed to be active.

TABLE 5 Inhibition of hIL-6 mRNA Transcription IL-6 IL-6 IL-6 IL-6Example activity Example activity Example activity Example activityNumber (IC50 <30 μM) Number (IC50 <30 μM) Number (IC50 <30 μM) Number(IC50 <30 μM) 1 Not Active 4 Active 5 Active 6 Active 7 Active 13 Active14 Active 15 Active 17 Active 19 Active 21 Active 24 Not Active 25Active 26 Active 27 Active 28 Active 29 Active 30 Active 34 Active 38Active 39 Active 42 Active 43 Active 44 Not Active 46 Active 47 Active49 Active 50 Active 51 Active 52 Active 53 Active 54 Active 55 Active 56Active 60 Active 63 Active 64 Active 65 Active 66 Active 70 Active 72Active 73 Active 75 Active 78 Active 79 Active 82 Active 83 Active 84Active 87 Not Active 89 Not Active 91 Not Active 93 Not Active 94 NotActive 95 Active 96 Active 98 Active 99 Active 101 Active 102 Active 103Not Active 104 Active 105 Active 107 Active 108 Active 109 Active 111Active 112 Not Active 113 Active 117 Active 118 Active 119 Active 120Not Active 121 Active 122 Active 123 Active 124 Active 125 Active 126Active 127 Active 128 Active 129 Active 130 Active 131 Active 132 Active133 Not Active 134 Active 136 Active 137 Active 138 Active 139 Active141 Active 142 Active 146 Active 147 Active 148 Active 149 Active 151Active 162 Active 164 Not Active 165 Active 167 Active 168 Not Active169 Active 171 Active 172 Active 179 Active 180 Active 181 Not Active182 Active 185 Not Active 186 Active 187 Not Active 188 Active 189Active 190 Not Active 191 Not Active 192 Active 193 Active 194 Active198 Not Active 203 Active 205 Active 206 Active 207 Active 208 Active209 Active 210 Active 211 Active 212 Active 213 Active 214 Active 215Active 216 Active 217 Not Active 218 Active 219 Active 220 Active 221Not Active 222 Active 223 Active 226 Active 227 Active 228 Active 230Active 231 Active 233 Active 237 Active 238 Active 240 Active 241 Active242 Active 244 Active 247 Active 250 Active 251 Active 252 Active 254Active 256 Active 258 Active 263 Active 264 Active 267 Active 270 Active271 Active 272 Active 273 Active 274 Active — —

Example 279 Inhibition of IL-17 mRNA Transcription

In this example, hIL-17 mRNA in human peripheral blood mononuclear cellswas quantitated to measure the transcriptional inhibition of hIL-17 whentreated with a compound of the invention.

Human peripheral blood mononuclear cells were plated (2.0×10⁵ cells perwell) in a 96-well plate in 45 μL OpTimizer T Cell expansion mediacontaining 20 ng/ml IL-2 and penicillin/streptomycin. The cells weretreated with the test compound (45 μL. at 2× concentration), and thenthe cells were incubated at 37° C. for 1 h before addition of 10× stockOKT3 antibody at 10 ug/ml in media. Cells were incubated at 37° C. for 3h before the cells were harvested. At time of harvest, cells werecentrifuged (800 rpm, 5 min). Spent media was removed and cell lysissolution (70 μL) was added the cells in each well and incubated for 5-10min at room temperature, to allow for complete cell lysis anddetachment. mRNA was then prepared using the “mRNA Catcher PLUS plate”(Invitrogen), according to the protocol supplied. After the last wash,as much wash buffer as possible was aspirated without allowing the wellsto dry. Elution buffer (E3, 70 μL) was then added to each well. mRNA wasthen eluted by incubating the mRNA Catcher PLUS plate with ElutionBuffer for 5 min at 68° C. and then immediately placing the plate onice.

The eluted mRNA isolated was then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data wasanalyzed, normalizing the Ct values for hIL-17 to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

Compounds with an IC₅₀ value less than 30 μM were deemed to be active.

TABLE 6 Inhibition of hIL-17 mRNA Transcription Example IL-17 activity(IC50 < 30 μM) Example 128 Active Example 180 Active Example 219 ActiveExample 241 Active Example 247 Active Example 271 Active

Example 280 Inhibition of hVCAM mRNA Transcription

In this example, hVCAMmRNA in tissue culture cells is quantitated tomeasure the transcriptional inhibition of hVCAM when treated with acompound of the present disclosure.

Human umbilical vein endothelial cells (HUVECs) are plated in a 96-wellplate (4.0×10³ cells/well) in 100 μL EGM media and incubated for 24 hprior to the addition of the compound of interest. The cells arepretreated for 1 h with the test compound prior to stimulation withtumor necrosis factor-α. The cells are incubated for an additional 24 hbefore the cells are harvested. At time of harvest, the spent media isremoved from the HUVECs and rinsed in 200 μL PBS. Cell lysis solution(70 μl) is then added the cells in each well and incubated for ^(˜)5-10min at room temperature, to allow for complete cell lysis anddetachment. mRNA is then prepared using the “mRNA Catcher PLUS plate”(Invitrogen), according to the protocol supplied. After the last wash,as much wash buffer as possible is aspirated without allowing the wellsto dry. Elution buffer (E3, 70 μL) is then added to each well. mRNA isthen eluted by incubating the mRNA Catcher PLUS plate with elutionbuffer for 5 min at 68° C. and then immediately placing the plate onice.

The eluted mRNA so isolated is then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data wasanalyzed, normalizing the Ct values for hVCAM to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

Compounds with an IC₅₀ value less than 30 μM are deemed to be active.

Example 281 Inhibition of hMCP-1 mRNA Transcription

In this example, hMCP-1 mRNA in human peripheral blood mononuclear cellswas quantitated to measure the transcriptional inhibition of hMCP-1 whentreated with a compound of the present disclosure.

Human Peripheral Blood Mononuclear Cells were plated (1.0×10⁵ cells perwell) in a 96-well plate in 45 μL RPMI-1640 containing 10% FBS andpenicillin/streptomycin. The cells were treated with the test compound(45 μL at 2× concentration), and then the cells were incubated at 37° C.for 3 h before the cells were harvested. At time of harvest, cells weretransferred to V-bottom plates and centrifuged (800 rpm, 5 min). Spentmedia was removed and cell lysis solution (70 μL) was added the cells ineach well and incubated for 5-10 min at room temperature, to allow forcomplete cell lysis and detachment. mRNA was then prepared using the“mRNA Catcher PLUS plate” (Invitrogen), according to the protocolsupplied. After the last wash, as much wash buffer as possible wasaspirated without allowing the wells to dry. Elution buffer (E3, 70 μL)was then added to each well. mRNA was then eluted by incubating the mRNACatcher PLUS plate with Elution Buffer for 5 min at 68° C. and thenimmediately placing the plate on ice.

The eluted mRNA isolated was then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data wasanalyzed, normalizing the Ct values for hMCP-1 to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

Compounds with an IC₅₀ value less than 30 μM were deemed to be active.

TABLE 7 Inhibition of hMCP-1 mRNA Transcription MCP-1 activity MCP-1activity Example (IC50 < 30 μM) Example (IC50 < 30 μM) 27 Active  56Active 73 Active 128 Active 134 Active — —

Example 282 Up-Regulation of hApoA-1 mRNA Transcription

In this example, ApoA-I mRNA in tissue culture cells was quantitated tomeasure the transcriptional up-regulation of ApoA-I when treated with acompound of the present disclosure.

Huh7 cells (2.5×10⁵ per well) were plated in a 96-well plate using 100μL DMEM per well, (Gibco DMEM supplemented with penicillin/streptomycinand 10% FBS), 24 h before the addition of the compound of interest.After 48 h treatment, the spent media was removed from the Huh-7 cellsand placed on ice (for immediate use) or at −80° C. (for future use)with the “LDH cytotoxicity assay Kit II” from Abcam. The cells remainingin the plate were rinsed with 100 μL PBS.

Then 85 μL of cell lysis solution was added to each well and incubatedfor 5-10 min at room temperature, to allow for complete cell lysis anddetachment. mRNA was then prepared using the “mRNA Catcher PLUS plate”from Life Technologies, according to the protocol supplied. After thelast wash, as much wash buffer as possible was aspirated withoutallowing the wells to dry. Elution Buffer (E3, 80 μL) was then added toeach well. mRNA was then eluted by incubating the mRNA Catcher PLUSplate with Elution Buffer for 5 min at 68° C., and then 1 min at 4° C.Catcher plates with mRNA eluted were kept on ice for use or stored at−80° C.

The eluted mRNA isolated was then used in a one-step real-time PCRreaction, using components of the Ultra Sense Kit together with LifeTechnologies primer-probe mixes. Real-time PCR data was analyzed, usingthe Ct values, to determine the fold induction of each unknown sample,relative to the control (that is, relative to the control for eachindependent DMSO concentration).

Compounds with an EC₁₇₀ value less than 30 μM were deemed to be active.

TABLE 8 Up-regulation of hApoA-1 mRNA Transcription. ApoA-1 ApoA-1ApoA-1 ApoA-1 Example activity Example activity Example activity Exampleactivity Number (EC₁₇₀ <30 μM) Number (EC₁₇₀ <30 μM) Number (EC₁₇₀ <30μM) Number (EC₁₇₀ <30 μM) 5 Active 6 Active 7 Active 13 Active 14 Active16 Active 17 Active 19 Active 43 Active 47 Active 49 Active 50 Active 51Active 52 Active 53 Active 54 Active 55 Active 56 Active 60 Active 66Active 72 Active 73 Active 75 Active 82 Active 83 Active 99 Active 104Active 105 Active 108 Active 109 Active 111 Active 112 Active 117 Active118 Active 119 Active 125 Active 128 Active 132 Active 134 Active 146Active 147 Active 148 Active 149 Active 155 Active 157 Active 158 Active160 Active 162 Active 179 Active 180 Active 181 Active 182 Active 183Active 184 Active 185 Active 186 Active 189 Active 190 Active 191 Active192 Active 193 Active 194 Active 198 Active 203 Active 205 Active 206Active 207 Active 208 Active 209 Active 210 Active 211 Active 212 Active213 Active 214 Active 215 Active 216 Active 217 Active 218 Active 219Active 220 Active 222 Active 223 Active 226 Active 227 Active 228 Active230 Active 233 Active 241 Active

Example 283 In Vivo Efficacy in Athymic Nude Mouse Strain of an AcuteMyeloid Leukemia Xenograft Model Using MV4-11 Cells

MV4-11 cells (ATCC) are grown under standard cell culture conditions and(NCr) nu/nu fisol strain of female mice age 6-7 weeks were injected with5×10⁶ cells/animal in 100 μl PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 18-21 after MV4-11 cellsinjection, mice are randomized based on tumor volume (L×Wx H)/2) ofaverage ^(˜)100-300 mm³. Mice are dosed orally with compound at 5 to 120mg/kg b.i.d and or 30 mg/kg q.d in EA006 formulation at 10 mL/kg bodyweight dose volume. Tumor measurements are taken with electronic microcalipers and body weights measured on alternate days beginning fromdosing period. The average tumor volumes, percent Tumor GrowthInhibition (TGI) and % change in body weights are compared relative toVehicle control animals. The means, statistical analysis and thecomparison between groups are calculated using Student's t-test inExcel.

Examples 284 In Vivo Efficacy in Athymic Nude Mouse Strain of an AcuteMyeloid Leukemia Xenograft Model Using OCI-3 AML Cells

OCl-3 AML cells (DMSZ) are grown under standard cell culture conditionsand (NCr) nu/nu fisol strain of female mice age 6-7 weeks are injectedwith 10×10⁶ cells/animal in 100 μL PBS+100 μL Matrigel in the lower leftabdominal flank. By approximately day 18-21 after OCl-3 AML cellsinjection, mice are randomized based on tumor volume (L×W×H)/2) ofaverage ^(˜)300 mm³. Mice are dosed orally with compound at 30 mg/kgb.i.d in EA006 formulation at 10 mL/kg body weight dose volume. Tumormeasurements are taken with electronic micro calipers and body weightsmeasured on alternate days beginning from dosing period. The averagetumor volumes, percent Tumor Growth Inhibition (TGI) and % change inbody weights are compared relative to Vehicle control animals. Themeans, statistical analysis and the comparison between groups arecalculated using Student's t-test in Excel.

Example 285 In Vivo Efficacy in Athymic Nude Mouse Strain of MultipleMyeloma Xenograft Model Using MM1.s Cells

MM1.s cells (ATCC) were grown under standard cell culture conditions andSCID-Beige strain of female mice age 6-7 weeks were injected with 10×10⁶cells/animal in 100 μl PBS+100 μL Matrigel in the lower left abdominalflank. By approximately day 21 after MM1.s cells injection, mice wererandomized based on tumor volume (L×Wx H)/2) of average ^(˜)120 mm³.Mice were dosed orally with compound at 25 to 90 mg/kg b.i.d in EA006formulation at 10 mL/kg body weight dose volume. Tumor measurements weretaken with electronic micro calipers and body weights measured onalternate days beginning from dosing period. The average tumor volumes,percent Tumor Growth Inhibition (TGI) and % change in body weights werecompared relative to Vehicle control animals. The means, statisticalanalysis and the comparison between groups were calculated usingStudent's t-test in Excel.

TABLE 9 In vivo efficacy in athymic nude mouse strain of multiplemyeloma xenograft model using MM1.s cells Example In vivo activityExample 152 Active

Example 286 In Vivo Efficacy in Mouse Endotoxemia Model Assay

Sub lethal doses of Endotoxin (E. Coli bacterial lipopolysaccharide)were administered to animals to produce a generalized inflammatoryresponse which was monitored by increases in secreted cytokines.Compounds were administered to C57/B16 mice orally at 75 mg/kg dose toevaluate inhibition in IL-6 and IL-17 cytokines post 4-h challenge withlipopolysaccharide (LPS) at 0.5 mg/kg dose intraperitoneally.

TABLE 10 In Vivo Efficacy in Mouse Endotoxemia Model Assay. Example Invivo activity Example 128 Active Example 56 Active

Example 287 In Vivo Efficacy in Rat Collagen-Induced Arthritis

Rat collagen-induced arthritis is an experimental model of polyarthritisthat has been widely used for preclinical testing of numerousanti-arthritic agents. Following administration of collagen, this modelestablishes a measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation. In this model,collagen was administered to female Lewis strain of rats on Day 1 and 7of study and dosed with compounds from Day 11 to Day 17. Test compoundswere evaluated to assess the potential to inhibit the inflammation(including paw swelling), cartilage destruction and bone resorption inarthritic rats, using a model in which the treatment is administeredafter the disease has been established.

TABLE 11 In Vivo Efficacy in Rat Collagen-Induced Arthritis. Example Invivo activity Example 128 Active

Example 288 In Vivo Efficacy in Experimental autoimmuneencephalomyelitis (EAE) Model of MS

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediatedautoimmune disease of the CNS which shares many clinical andhistopathological features with human multiple sclerosis (MS). EAE isthe most commonly used animal model of MS. T cells of both Th1 and Th17lineage have been shown to induce EAE. Cytokines IL-23, IL-6 and IL-17,which are either critical for Th1 and Th17 differentiation or producedby these T cells, play a critical and non-redundant role in EAEdevelopment. Therefore, drugs targeting production of these cytokinesare likely to have therapeutic potential in treatment of MS.

This study may be conducted to assess the potential anti-inflammatoryeffect of test compounds to inhibit the inflammation and clinical EAEscores of a 28 day preventative mouse model. In this model, EAE isinduced by MOG₃₅₋₅₅/CFA immunization and pertussis toxin injection infemale C57Bl/6 mice.

In view of the preceding disclosure and examples, the invention includesat least the following exemplary embodiments:

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof,wherein:

-   -   W₁ is selected from N and CR₅;    -   W₂ is selected from N and CR₄;    -   W₃ is selected from N and CR₃;    -   each W may be the same or different from each other;    -   R₁ is selected from a carbocycles or heterocycles;    -   R₂ is selected from a 5- or 6-membered monocyclic carbocycle or        a 5- or 6-membered monocyclic heterocycle;    -   R₃, R₄, and R₅ are each independently selected from hydrogen,        alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, carbonate, amino, amide, halogen,        carbocycle, heterocycle, sulfone, sulfoxide, sulfide,        sulfonamide, and —CN;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle;    -   R₄ may be connected to B or R₂ to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)CR_(Z)R_(v)CR_(Q)R_(R)—;    -   R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or two substituents selected from        R_(x), R_(y), R_(z), R_(v), R_(S), and R₁ may be connected in a        5- or 6-membered ring to form a bicyclic carbocycle or bicyclic        heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent and        R₂ is connected directly to the center ring;        R_(a), R_(b), R_(c), and R_(d) are each independently selected        from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

2. A compound of Formula II:

or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydratethereof,wherein:

-   -   W₁ is selected from N and CR₅;    -   W₂ is selected from N and CR₄;    -   W₃ is selected from N and CR₃, with the proviso that if W₃ is N        then neither R₅ nor R₄ is —OH;    -   each W may be the same or different from each other;    -   R₁ is a carbocycle or heterocycle;    -   V is selected from a 5-membered monocyclic carbocycle or        monocyclic heterocycle, where the heterocycle is connected to        the rest of the molecule via a carbon-carbon bond,    -   with the proviso that V cannot be unsubstituted thiophene,        cyclopentyl, cyclopentenyl, ribofuranosyl, or furan,    -   R₃, R₄, and R₅ are each independently selected from hydrogen,        alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, carbonate, amino, amide, halogen,        carbocycle, heterocycle, sulfone, sulfoxide, sulfide,        sulfonamide, and —CN,    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle;    -   R₄ may be connected to B or V to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)CR_(z)R_(y)CR_(Q)R_(R)—,    -   with the proviso that R_(x) and R_(y) cannot both be an        unsubstituted phenyl ring,    -   and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then        R₄ is not —OH,    -   and with the proviso that if A is —CH₂CH₂O— or —CH₂C(O)NH— then        V is not a substituted

-   -    or a substituted

-   -   and with the proviso that if A is —CH₂CH₂O— then R₁ is not

-   -   R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or two substituents selected from        R_(x), R_(y), R_(z), R_(v), R₅, and R₁ may be connected in a 5-        or 6-membered ring to form a bicyclic carbocycle or bicyclic        heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —S—, —SCR_(a)R_(b)—, —CR_(a)R_(b)S—,        —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—, —SO₂—,        —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent; and        wherein    -   R_(a), R_(b), R_(c), and R_(d) are each independently selected        from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

3. The compound according to embodiment 2, wherein if W₁═CR₅ and V is anoptionally substituted

then at least one of R₃ and R₄ are not hydrogen.

4. The compound according to embodiment 2, wherein if W₃═N, then R₄ isnot hydrogen.

5. The compound according to embodiment 2, wherein if W₁═CR₅ and V is

then R₁ is not

6. The compound according to embodiment 2, wherein if W₁═CR₅ and V is

then R₁ is not

7. The compound according to embodiment 2, wherein if W₁═N and V is anoptionally substituted

then at least one of R₃ and R₄ are not hydrogen.

8. The compound according to embodiment 2, wherein if W₃═N, then R₄ isnot hydrogen.

9. The compound according to embodiment 2, wherein if W₁═N and V is anoptionally substituted

then R₁-A is not

10. The compound according to embodiment 2, wherein if W₁═N and V is

then R₃ and R₄ cannot be connected to form

11. The compound according to embodiment 2, wherein if R₅ is —COOMe thenV is not a substituted thiophene.

12. The compound according to embodiment 2, wherein if R₅ is methyl thenR₂ is not

13. The compound according to embodiment 2, wherein if B is present thenneither R₄ nor R₅ is hydroxyl.

14. The compound according to embodiment 2, wherein R_(x) and R_(y)cannot both be an unsubstituted phenyl ring.

15. The compound according to any one of embodiments 2 to 14, wherein Vis selected from an optionally substituted 5-membered monocyclicheterocycle selected from

16. The compound according to any one of embodiments 2 to 14, wherein Vis optionally substituted with hydrogen, alkyl (C₁-C₄)(such as methyl,ethyl, propyl, isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy,ethoxy, isopropoxy), amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu—NMe₂, NMeEt, —NEt₂, —NEtBu), —NHC(O)NHalkyl), halogen (such as F, Cl),amide (such as —NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr),—CF₃, CN, —N₃, ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr),—S(O)Alkyl(C₁-C₄) (such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as—SO₂Me, —SO₂Et, —SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr,—SBu), carboxyl (such as —COOH), ester (such as —C(O)OMe, —C(O)OEt,—C(O)OBu), each of which may be optionally substituted with hydrogen, F,Cl, Br, —OH, —NH₂, —NHMe, —OMe, —SMe, oxo, and thio-oxo.

17. The compound according to any one of embodiments 2 to 14, wherein Vis selected from an optionally substituted 5-membered monocyclicheterocycle containing one oxygen and one or two nitrogens, where theheterocycle is connected to the rest of the molecule via a carbon-carbonbond.

18. The compound according to any one of embodiments 2 to 14, wherein Vis an optionally substituted isoxazole.

19. The compound according to any one of embodiments 2 to 14, wherein Vis

20. The compound according to any one of embodiments 2 to 14, wherein W₁is CR_(s).

21. The compound according to any one of embodiments 2 to 14, wherein W₂is CR₄.

22. The compound according to any one of embodiments 2 to 14, wherein Xis oxygen.

23. The compound according to any one of embodiments 2 to 14, whereinn=0, meaning B is absent.

24. The compound according to any one of embodiments 2 to 14, wherein Ais selected from C═O and —CR_(x)R_(y)—.

25. The compound according to any one of embodiments 2 to 14, wherein R₁is selected from an optionally substituted 3-, 4-, 5-, and 6-memberedcarbocycle or heterocycle.

26. The compound according to embodiment 25, wherein the carbocycle orheterocycle is selected from cyclopropyl, phenyl, pyridyl, thiophene,cyclobutyl, piperidine, piperazine, cyclopentyl, and cyclohexyl.

27. The compound according to embodiment 25, wherein R₁ is selected froman optionally substituted 5- and 6-membered carbocycle or heterocycle.

28. The compound according to embodiment 27, wherein the carbocycle orheterocycle is selected from phenyl, pyridyl, thiophene, andcyclopentyl.

29. The compound according to embodiment 28, wherein R₁ is selected froman optionally substituted phenyl or pyridyl ring.

30. The compound according to any one of embodiments 2 to 14, whereinR₃, R₄, and R₅ are each independently selected from hydrogen, alkyl(C₁-C₈), —OH, —NH₂, thioalkyl (C₁-C₈), alkoxy(C₁-C₈) (such as methoxy,ethoxy, —OPr, -OiPr), ketone(C₁-C₈), ester, carboxylic acid, urea,carbamate, carbonate, amino, amide, halogen (such as F, Cl, Br),carbocycle (such as cyclopropyl, cyclopentyl, phenyl), alkenyl(C₁-C₈),alkynyl (C₁-C₈), heterocycle, sulfone, sulfoxide, sulfide, sulfonamide,and —CN, any of which may be optionally substituted.

31. The compound according to any one of embodiments 2 to 14, wherein R₅is selected from hydrogen, methyl, —CF₃, Ethyl, propyl, isopropyl,methoxy, ethoxy, propoxy, —NHMe, —NHEthyl, —NHAc, NH₂, and —CN.

32. The compound according to any one of embodiments 2 to 14, wherein R₃is selected from hydrogen, —CN, —NH₂, amino (such as —NHMe, —NHethyl,—NHcyclopropyl, —NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), amido(such as —NHAc, —NHC(O)Et, —NHC(O)Pr, —NHC(O)phenyl, —C(O)NHMe,—C(O)NH₂, —C(O)NHEt, —C(O)NMe₂), sulfone, Sulfoxide, sulfonamide (suchas —SO₂NH₂, —NHSO₂Me), carbocycle (phenyl, cyclopropyl, cyclobutyl,cyclopentyl), and heterocycle, any of which may be optionallysubstituted.

33. The compound according to any one of embodiments 2 to 14, wherein R₃is selected from hydrogen, —NH₂, amino (such as —NHMe, —NHEt,—NHcyclopropyl, —NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), and—NHheterocycle or heterocycle selected from

any of which may be optionally substituted with groups independentlyselected from hydrogen, alkyl (C₁-C₃), —OH, —NH₂, thioalkyl (C₁-C₃),alkoxy (C₁-C₃), ketone (C₁-C₃), ester, carboxylic acid, urea, carbamate,carbonate, amino, amide, and halogen.

34. The compound according to embodiment 33, wherein R₃ is selected fromhydrogen, —NH₂, and amino.

35. The compound according to any one of embodiments 2 to 14, wherein R₃and R₄ are connected to form an optionally substituted 5-, 6-, or7-membered carbocycle or heterocycle selected from

36. The compound according to any one of embodiments 2 to 14, whereinR_(x) and R_(y) are selected from hydrogen, alkyl(C₁-C₃); halogen (suchas F and Cl), —CF₃, amino (such as —NHMe, —NHEt, —NHiPr), alkoxy (suchas —OMe, OEt, OPr), —CN.

37. The compound according to any one of embodiments 2 to 14, whereinR_(a), R_(b), R_(c) and R_(d) are independently selected from hydrogen,methyl, methoxy, and —CF₃.

38. The compound according to any one of embodiments 2 to 14, wherein Bis selected from —(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, —S(O)—, —SO₂—,where n is 0 or 1, meaning if n=0 then B is absent.

39. The compound according to any one of embodiments 2 to 14, whereinthe compound of Formula II is selected from:

-   6-(3,5-Dimethylisoxazol-4-yl)-2-phenethylpyridazin-3(2H)-one    (Example 1);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(pyridin-2-ylmethyl)pyridazin-3(2H)-one    (Example 2);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(pyrimidin-2-ylmethyl)pyridazin-3(2H)-one    (Example 3);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 4);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one    (Example 5);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyrazin-2(1H)-one (Example 6);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 7);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2(1H)-one (Example    8);-   1-(4-((Dimethylamino)methyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    hydrochloric acid (Example 9);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one    hydrochloric acid (Example 10);-   5-(3,5-Dimethylisoxazol-4-yl)-1-((3,5-dimethylisoxazol-4-yl)methyl)pyridin-2(1H)-one    (Example 11);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methylpyridin-2(1H)-one    (Example 12);-   4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzamide    (Example 13);-   2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one (Example    14);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(quinoxalin-6-ylmethyl)pyridin-2(1H)-one    (Example 18);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one    (Example 19);-   2-Benzyl-4-methyl-6-(5-methylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 20);-   2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one    (example 21);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluorobenzyl)pyridazin-3(2H)-one    (Example 22);-   2-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 23);-   2-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)benzonitrile    (Example 24);-   2-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 25);-   2-(2-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 26);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one    (Example 27);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-methylbenzyl)pyridazin-3(2H)-one    (Example 28);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methylbenzyl)pyridazin-3(2H)-one    (Example 29);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methylbenzyl)pyridazin-3(2H)-one    (Example 30);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one    (Example 31);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluoro-5-methylbenzyl)pyridazin-3(2H)-one    (Example 32);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methoxybenzyl)pyridazin-3(2H)-one    (Example 33);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridazin-3(2H)-one    (Example 34);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methoxybenzyl)pyridazin-3(2H)-one    (Example 35);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one    (Example 36);-   6-(3,5-Dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)pyridazin-3(2H)-one    (Example 37);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one    (Example 38);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one    (Example 39);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethoxy)benzyl)pyridin-2(1H)-one    (Example 40);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methylbenzyl)pyridin-2(1H)-one    (Example 41);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluorobenzyl)pyridin-2(1H)-one    (Example 42);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylpropyl)pyridin-2(1H)-one    (Example 43);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one    (Example 44);-   2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 45);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one    (Example 46);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(quinolin-8-ylmethyl)pyridin-2(1H)-one    (Example 47);-   1-(Cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 48);-   1-(Cyclobutylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 49);-   1-(3-(Difluoromethyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 50);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenoxyethyl)pyridin-2(1H)-one    (Example 51);-   1-((5-Chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 55);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one (Example    56);-   1-Benzyl-5-(5-methylisoxazol-4-yl)pyridin-2(1H)-one (Example 57);-   1-Benzyl-5-(isoxazol-4-yl)pyridin-2(1H)-one (Example 58);-   1-Benzyl-5-(isothiazol-4-yl)pyridin-2(1H)-one (Example 59);-   2-Benzyl-6-((3,5-dimethylisoxazol-4-yl)amino)pyridazin-3(2H)-one    (Example 61);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2(1H)-one    (Example 63);-   1-Benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 64);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methylpyridin-2(1H)-one    (Example 66);-   1-Benzyl-3-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 67);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzoyl)pyridin-2(1H)-one    (Example 68);-   1-(4-Chlorobenzoyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 69);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)pyridin-2(1H)-one    (Example 70);-   N-(1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide    (Example 71);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one    (Example 72);-   3-Amino-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 73);-   1-Benzyl-3-(benzylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 74);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(methylamino)pyridin-2(1H)-one    (Example 75);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one    (Example 76);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(naphthalen-2-ylmethyl)pyridazin-3(2H)-one    (Example 77);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methoxybenzyl)pyridin-2(1H)-one    (Example 78);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one    (Example 79);-   1-Benzyl-5-(thiazol-5-yl)pyridin-2(1H)-one (Example 80);-   1-Benzyl-5-(5-methyl-1H-imidazol-4-yl)pyridin-2(1H)-one (Example    81);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)-4-methylpyridazin-3(2H)-one    (Example 84);-   2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one    (Example 85);-   2-Benzyl-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one    (Example 86);-   6-(3,5-Dimethylisoxazol-4-yl)-4-methyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one    (Example 87);-   2-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 88);-   4-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)-N-methylbenzamide    (Example 89);-   2-(2,6-Difluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 90);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one    (Example 91);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2,4,6-trifluorobenzyl)pyridazin-3(2H)-one    (Example 92);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)pyridazin-3(2H)-one    (Example 93);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H)-one    (Example 94);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-fluorophenyl)ethyl)pyridazin-3(2H)-one    (Example 95);-   2-(2-Chloro-6-fluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 96);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(isoxazol-4-ylmethyl)pyridazin-3(2H)-one    (Example 97);-   5-(5-Amino-3-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one    trifluoroacetic acid (Example 98);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 101);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(quinolin-8-ylmethyl)pyridazin-3(2H)-one    (Example 102);-   1-(1-(2-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 103);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 104);-   1-(1-(4-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 105);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenylpropan-2-yl)pyridin-2(1H)-one    (Example 106);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(thiophen-3-ylmethyl)pyridazin-3(2H)-one    (Example 107);-   (R)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one    (Example 108);-   (S)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one    (Example 109);-   (S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 110);-   (R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 111);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one    (Example 112);-   1-(1-(3-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 113);-   1-Benzyl-6-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 114);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-6-methylpyridin-2(1H)-one    (Example 115);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methylbenzyl)pyridin-2(1H)-one    (Example 121);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methylbenzyl)pyridin-2(1H)-one    (Example 122);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 123);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-fluorophenyl)ethyl)pyridin-2(1H)-one    (Example 124);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 125);-   1-(3-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 126);-   1-(2-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 127);-   1-(4-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 128);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one    (Example 129);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one    (Example 130);-   1-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 131);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one    (Example 132);-   (S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 133);-   (R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 134);-   2-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile    (Example 135);-   1-(2,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 136);-   4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile    (Example 137);-   1-(2,4-Difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 138);-   1-(4-Chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 139);-   1-(2-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 140);-   1-(4-Chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 141);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(3,4,5-trifluorobenzyl)pyridin-2(1H)-one    (Example 142);-   2-((1H-Benzo[d]imidazol-5-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 143);-   6-(3,5-Dimethylisoxazol-4-yl)-2-(3,4,5-trifluorobenzyl)pyridazin-3(2H)-one    (Example 144);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(methylsulfonyl)benzyl)pyridin-2(1H)-one    (Example 145);-   1-((1H-Benzo[d]imidazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 146);-   1-(3-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 147);-   1-((1H-Indazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 148);-   1-((1H-Indol-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 149);-   1-((4-Chlorophenyl)sulfonyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 150);-   5-(3-Amino-5-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one (Example    151);-   3-Amino-1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 152);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-methylpiperazin-1-yl)pyridin-2(1H)-one    Hydrochloride (Example 153);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methoxypyridin-2(1H)-one    (Example 154);-   1-(3,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 155);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((4-fluorophenyl)amino)pyridin-2(1H)-one    (Example 156);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3-fluorophenyl)amino)pyridin-2(1H)-one    (Example 157);-   1-Benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 158);-   1-(4-Chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 159);-   1-Benzyl-5-(3-methylisothiazol-4-yl)pyridin-2(1H)-one (Example 160);-   1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(piperazin-1-yl)pyridin-2(1H)-one    Hydrochloride (Example 161);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methoxybenzyl)pyridin-2(1H)-one    (Example 162);-   5-(3,5-Dimethylisoxazol-4-yl)-1-(pyrimidin-2-ylmethyl)pyridin-2(1H)-one    (Example 163);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one (Example    167);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2H-phthalazin-1-one (Example    170);-   6-Benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one    (Example 173);-   7-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one    (Example 174);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one    (Example 175);-   2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one    (Example 176);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one    (Example 180);-   3-chloro-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one    (Example 181);-   5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-(phenylamino)pyridin-2(1H)-one    (Example 182);-   3-(azetidin-1-yl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 183);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((1-methyl-1H-pyrazol-3-yl)amino)pyridin-2(1H)-one    (Example 184);-   3-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide    (Example 185);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(ethylamino)pyridin-2(1H)-one    (Example 186);-   1-benzyl-5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 187);-   1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one    (Example 188);-   3-amino-1-benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 189);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-morpholinopyridin-2(1H)-one    (Example 190);-   1-benzyl-3-(benzyloxy)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 191);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(isopropylamino)pyridin-2(1H)-one    (Example 192);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylamino)pyridin-2(1H)-one    (Example 193);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-3-ylamino)pyridin-2(1H)-one    (Example 194);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-4-ylamino)pyridin-2(1H)-one    (Example 195);-   1-benzyl-5-(3,5-dimethylisothiazol-4-yl)pyridin-2(1H)-one (Example    196);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile    (Example 198);-   methyl    4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylate    (Example 199);-   N-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methanesulfonamide    (Example 200);-   2-benzyl-6-(((3,5-dimethylisoxazol-4-yl)methyl)amino)pyridazin-3(2H)-one    (Example 201);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxamide    (Example 202);-   3-amino-1-(4-chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 203);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(1H-imidazol-1-yl)pyridin-2(1H)-one    (Example 204);-   3-amino-1-(4-chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 205);-   3-amino-1-(4-chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 206);-   3-amino-1-(2-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 207);-   1-benzyl-3-(cyclopentylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 208);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-hydroxypyridin-2(1H)-one    (Example 209);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methoxypyridin-2(1H)-one    (Example 210);-   3-amino-1-(3,4-difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 211);-   3-amino-1-(3-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 212);-   3-amino-1-(3,4-dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 213);-   1-benzyl-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-2(1H)-one    (Example 214);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-2-ylmethyl)pyridin-2(1H)-one    (Example 215);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile    (Example 216);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3,5-dimethylisoxazol-4-yl)amino)pyridin-2(1H)-one    (Example 217);-   5-(3,5-dimethylisoxazol-4-yl)-1-(4-vinylbenzyl)pyridin-2(1H)-one    (Example 218);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one    (Example 219);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one    (Example 220);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridazin-3-ylamino)pyridin-2(1H)-one    (Example 221);-   3-amino-1-((5-chlorothiophen-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 222);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-fluoropyridin-3-yl)amino)pyridin-2(1H)-one    (Example 223);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-methylpyridin-2(1H)-one    (Example 224);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylic    acid (Example 225);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one    (Example 226);-   3-amino-1-(2-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 227);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one    (Example 228);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic    acid (Example 229);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide    (Example 230);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methoxypyridin-3-yl)amino)pyridin-2(1H)-one    (Example 231);-   5-O-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)picolinonitrile    (Example 232);-   4-amino-2-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 233);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methoxypyridin-3-yl)amino)pyridin-2(1H)-one    (Example 234);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrazin-2-ylamino)pyridin-2(1H)-one    (Example 235);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrimidin-5-ylamino)pyridin-2(1H)-one    (Example 236);-   3-amino-1-(4-(azetidin-1-yObenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 237);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-morpholinobenzyl)pyridin-2(1H)-one    (Example 238);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrrolidin-3-ylamino)pyridin-2(1H)-one    (Example 239);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)pyridin-2(1H)-one    (Example 240);-   3-amino-1-(4-bromobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 241);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-isopropylbenzyl)pyridin-2(1H)-one    (Example 242);-   1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-((2,2,2-trifluoroethyl)amino)pyridin-2(1H)-one    (Example 243);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one    (Example 244);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methylpyridin-3-yl)amino)pyridin-2(1H)-one    (Example 245);-   1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methylpyridin-3-yl)amino)pyridin-2(1H)-one    (Example 246);-   1-((1H-indol-4-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 247);-   2-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one    (Example 248);-   4-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methoxy-N,5-dimethylisoxazole-3-carboxamide    (Example 249);-   4-amino-2-benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one    (Example 250);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((2,5-dimethylthiophen-3-yl)methyl)pyridin-2(1H)-one    (Example 251);-   3-amino-1-((5-chloropyridin-3-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 252);-   3-amino-1-((3-chloropyridin-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 253);-   3-amino-1-((3-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 254);-   3-amino-1-((5-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 255);-   3-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 256);-   3-amino-1-(benzo[d][1,3]dioxol-4-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 257);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-3-yl)methyl)pyridin-2(1H)-one    (Example 258);-   methyl    4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylate    (Example 259);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylic    acid (Example 260);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-fluorobenzonitrile    (Example 261);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-fluorobenzonitrile    (Example 262);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one    (Example 263);-   5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)thiophene-2-carbonitrile    (Example 264);-   4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-N,3-dimethylisoxazole-5-carboxamide    (Example 265);-   3-(aminomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 266);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-iodobenzyl)pyridin-2(1H)-one    (Example 267);-   1-benzyl-5-(5-oxopyrrolidin-3-yl)pyridin-2(1H)-one (Example 268);-   4-(1-(3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile    (Example 269);-   1-((1H-indol-3-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one    (Example 270);-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methyl-1H-indol-4-yl)methyl)pyridin-2(1H)-one    (Example 271);-   5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile    (Example 272);-   4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile    (Example 276); and-   3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(quinolin-5-ylmethyl)pyridin-2(1H)-one    (Example 274).

40. A compound of Formula III:

-   -   or a stereoisomer, tautomer, pharmaceutical acceptable salt, or        hydrate thereof,    -   wherein:    -   W₂ is selected from N and CR₄,    -   W₃ is selected from N and CR₃,    -   each W may be the same or different from each other;    -   R₁ is a carbocycle or heterocycle,    -   R₂ is selected from a 6-membered monocyclic carbocycle or        monocyclic heterocycle,    -   R₃, R₄, and R₅ are each independently selected from hydrogen,        alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic        acid, urea, carbamate, carbonate, amino, amide, halogen,        carbocycle, heterocycle, sulfone, sulfoxide, sulfide,        sulfonamide, and —CN,    -   with the proviso that R₄ is not —OH and R₅ is not —COOH or        -ester;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle;    -   R₄ may be connected to B or R₂ to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(y)N—, —CR_(x)R_(y)CR_(z)R_(y)S—, and        —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R);    -   with the proviso that R_(x) and R_(y) cannot both be an        unsubstituted phenyl ring, and with the proviso that if A is        —CH₂CH₂CH₂— and W₃ is N then R₄ is not —OH,    -   and with the proviso that if A is —CH₂CH₂O— then R₁ is not

-   -   R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(y), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or two substituents selected from        R_(x), R_(y), R₂, R_(v), R_(S), and R₁ may be connected in a 5-        or 6-membered ring to form a bicyclic carbocycle or bicyclic        heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent;        and R_(a), R_(b), R_(c), and R_(d) are each independently        selected from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

41. The compound according to embodiment 40, wherein if W₂ is N and R₂is

then R₅ is not hydrogen.

42. The compound according to embodiment 40, wherein if W₃ is N thenneither R₅ nor R₄ is —OH.

43. The compound according to embodiment 40, wherein R₁-A is not

44. The compound according to embodiment 40, wherein if R₁-A is

then at least one of Q₁, O₂, Q₃, or Q₄ is not hydrogen.

45. The compound according to embodiment 40, wherein if R₁-A is

then at least one of R₃ and R₄ is not hydrogen.

46. The compound according to embodiment 40, wherein if R₁ is

then R₂ is not

47. The compound according to embodiment 40, wherein if R₁ is

then R₂ is not

48. The compound according to embodiment 40, wherein R₂ is not

or an optionallysubstituted

49. The compound according to embodiment 40, wherein if R₂ is

then at least one of R₃ and R₄ is not hydrogen

50. The compound according to embodiment 40, wherein if R₃ is —CN, thenR₂ is not

51. The compound according to embodiment 40, wherein if R₂ is

then R₁ is not

or if R₂ is

then R₅ is not —COOMe; or if R₄ is —NH₂ then R₂ is not

52. The compound according to any one of embodiments 40 to 51, whereinR₂ is selected from an optionally substituted 6-membered monocycliccarbocycle (such as phenyl) or heterocycle (such as pyridyl, pyrimidine,pyrazine, and triazine), where the heterocycle is connected to the restof the molecule via a carbon-carbon bond.

53. The compound according to any one of embodiments 39 to 50, whereinR₂ is selected from

wherein:W_(a) is selected from N and CQ₁;W_(b) is selected from N and CQ₂;W_(c) is selected from N and CQ₃;W_(d) is selected from N and CQ₄;W_(e) is selected from N and CQ₅;Each W may be the same or different from each other;Q₁, Q₂, Q₄, Q₅ are each independently selected from hydrogen, —OH, —NH₂,halogen, —CF₃, —CN, —Ac, alkyl(C₁-C₃), alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃), —N(Alkyl)₂ (C₁-C₃),which may be optionally substituted with groups independently selectedfrom F, Cl, Br, —OH, —NH₂, —OMe, —OEt, —NHMe, —SMe, —S(O)Me, -Me, and-Et;Q₃ is selected from —OH, —NH₂, F, Cl, alkyl(C₁-C₃), alkoxy(C₁-C₃),—S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃),and —N(Alkyl)₂ (C₁-C₃), which may be optionally substituted with groupsindependently selected from F, Cl, —OH, —NH₂, —OMe, —OEt, -Me, and -Et.

54. The compound according to any one of embodiments 40 to 51, whereinR₂ is selected from

55. The compound according to any one of embodiments 40 to 51, whereinR₁ is selected from a 3, 4-, 5-, or 6-membered carbocycle orheterocycle.

56. The compound according to embodiment 55, wherein R₁ is selected froman optionally substituted phenyl.

57. The compound according to any one of embodiments 40 to 51, whereinR₁ is optionally substituted with hydrogen, —OH, —NH₂, halogen, —CF₃,—CN, —Ac, Alkyl(C₁-C₃), Alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —SAlkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂(C₁-C₃), any of which may be optionally substituted.

58. The compound according to any one of embodiments 40 to 51, whereinR₃ is selected from hydrogen, —CN, —NH₂, amino (such as —NHMe, —NHethyl,—NHcyclopropyl, —NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), amido(such as —NHAc, —NHC(O)Et, —NHC(O)Pr, —NHC(O)phenyl, —C(O)NHMe,—C(O)NH₂, —C(O)NHEt, —C(O)NMe₂), sulfone, Sulfoxide, sulfonamide (suchas —SO₂NH₂, —NHSO₂Me), carbocycle (phenyl, cyclopropyl, cyclobutyl,cyclopentyl), or heterocycle, any of which may be optionallysubstituted.

59. The compound according to any one of embodiments 40 to 51, whereinR₃ is selected from hydrogen, —NH₂, amino (such as —NHMe, —NHEt,—NHcyclopropyl, —NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), and—NHheterocycle or heterocycle (such as,

any of which may be optionally substituted with groups independentlyselected from hydrogen, alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, carbonate, amino, amide,halogen, oxo, and thio-oxo.

60. The compound according to any one of embodiments 40 to 51, whereinR₃, R₄, and R₅ may be optionally substituted with groups independentlyselected from hydrogen, alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, carbonate, amino, amide, andhalogen.

61. The compound according to any one of embodiments 40 to 51, whereinR₃ and R₄ may be connected to form an optionally substituted 5-, 6-, or7-membered carbocycle or heterocycle such as

62. The compound according to any one of embodiments 40 to 51, whereinR₅ is hydrogen.

63. The compound according to any one of embodiments 40 to 51, whereinR₄ is hydrogen.

64. The compound according to any one of embodiments 40 to 51, wherein Xis oxygen.

65. The compound according to any one of embodiments 40 to 51, whereinn=0, meaning B is absent.

66. The compound according to any one of embodiments 40 to 51, wherein Bis selected from —(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, where n is 0 or 1,meaning if n=0 then B is absent.

67. The compound according to any one of embodiments 40 to 51, wherein Ais selected from C═O and —CR_(x)R_(y)—.

68. The compound according to any one of embodiments 40 to 51, whereinthe compound of Formula III is selected from:

-   1-Benzyl-5-(3,4,5-trimethoxyphenyl)pyridin-2(1H)-one (Example 52);-   2-((2-Oxo-5-(3,4,5-trimethoxyphenyl)pyridin-1(2H)-yl)methyl)benzonitrile    (Example 53);-   1-Benzyl-2′-hydroxy-[3,4′-bipyridin]-6(1H)-one (Example 62);-   1-Benzyl-5-((3,4-dimethoxyphenyl)amino)pyridin-2(1H)-one (Example    65);-   2-Benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one (Example 166);-   2-Benzyl-4-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one (Example    168);-   2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)isoquinolin-1(2H)-one (Example    169); and-   2-Benzyl-4-((3,4,5-trimethoxyphenyl)amino)isoquinolin-1(2H)-one    (Example 172).

69. A compound of Formula IV:

-   -   or a stereoisomer, tautomer, pharmaceutically acceptable salt,        or hydrate thereof,    -   wherein:    -   W₂ is selected from N and CR₄,    -   W₃ is selected from N and CR₃,    -   each W may be the same or different from each other;    -   R₁ is a carbocycle or heterocycle,    -   R₂ is selected from a 6-membered monocyclic carbocycle or        monocyclic heterocycle,    -   R₃ and R₄ are each independently selected from hydrogen, alkyl,        —OH, —NH₂, thioalkyl, alkoxy, ketone, ester, carboxylic acid,        urea, carbamate, carbonate, amino, amide, halogen, carbocycle,        heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN,    -   with the proviso that R₄ is not —OH;    -   R₃ and R₄ may be connected to form an optionally substituted 5-,        6-, or 7-membered carbocycle or heterocycle,    -   with the proviso that R₃ and R₄ are not connected to form

-   -   R₄ may be connected to B or R₂ to form a carbocycle or        heterocycle;    -   X is selected from O and S;    -   A is selected from —CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—,        —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—, —CR_(x)R_(y)CR_(z)R_(v)O—,        —CR_(x)R_(y)CR_(z)R_(v)N—, —CR_(x)R_(y)CR_(z)R_(v)S—, and        —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—;    -   with the proviso that if A is C═O, then R₂ is not an optionally        substituted

-   -    where T is halogen,    -   and with the proviso that R_(x) and R_(y) cannot both be an        unsubstituted phenyl ring,    -   and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then        R₄ is not —OH,    -   and with the proviso that if A is —CH₂CH₂O— then R₁ is not

-   -   R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each        independently selected from hydrogen, alkyl(C₁-C₈), halogen,        —OH, —CF₃, amino, alkoxy (C₁-C₈), carboxyl, —CN, sulfone,        sulfoxide, carbocycle, and heterocycle, or two substituents        selected from R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) may        form an oxo or thio-oxo group, or    -   two substituents selected from R_(x), R_(y), R_(z), R_(v), R₅,        and R₁ may be connected in a 5- or 6-membered ring to form a        bicyclic carbocycle or bicyclic heterocycle;    -   B is selected from —(CR_(a)R_(b))_(n)—,        —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—,        —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—,        —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—,        —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—;    -   n is selected from 0 and 1, meaning if n=0 then B is absent;        R_(a), R_(b), R_(c), and R_(d) are each independently selected        from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).

70. The compound according to embodiment 69, wherein if W₂ is N and R₂is

then R₅ is not hydrogen.

71. The compound according to embodiment 69, wherein if W₃ is N thenneither R₅ nor R₄ is —OH.

72. The compound according to embodiment 69, wherein R₁ is not an aminogroup with nitrogen attached to A, a substituted napthyl, or cyclohexyl.

73. The compound according to embodiment 69, wherein R₁-A is not

74. The compound according to embodiment 69, wherein if R₁-A is

then R₂ is not an optionally substituted

where T is halogen.

75. The compound according to embodiment 69, wherein if R₁-A is

then R₂ is not

76. The compound according to embodiment 69, wherein if R₁A is

then R₂ is not substituted with —OH or —NH₂.

77. The compound according to embodiment 68, wherein R₂ is not anunsubstituted thiophene, furan, cyclopentyl, cyclohexyl, or

where T is any atom.

78. The compound according to embodiment 69, wherein R₂ is not

where T is Cl, Br, —OMe, or Me.

79. The compound according to embodiment 69, wherein R₂ is not

where T and Y are independently selected from Cl, F, -Me, —CN, or —OH.

80. The compound according to embodiment 69, wherein R₂ is not

81. The compound according to embodiment 69, wherein if R₂ is

then R₁-A is not

where T and Y are independently selected from hydrogen, F, Cl, Br, —CF₃,and -Me, and R₁ is not unsubstituted pyridyl, substituted furan, orunsubstituted naphthyl.

82. The compound according to embodiment 69, wherein if R₂ is

where T is an —OH, Alkoxy, —OAcyl, —NH₂, amino, amide, carbamate, orurea substituent, then at least one of R₃ and R₄ is not hydrogen.

83. The compound according to embodiment 69, wherein if R₂ is anunsubstituted pyridyl, then at least one of R₃ and R₄ is not hydrogen,or R₁-A is not

or R₃ and R₄ are not connected to form an unsubstituted benzene ring.

84. The compound according to embodiment 69, wherein if R₂ is

then R₃ is not methyl, at least one of R₃ and R₄ cannot be connected to

or R₁-A cannot be

85. The compound according to any one of embodiments 69 to 84, whereinR₂ is selected from an optionally substituted 6-membered monocycliccarbocycle (such as phenyl) or heterocycle (such as pyridyl, pyrimidine,pyrazine, and triazine), where the heterocycle is connected to the restof the molecule via a carbon-carbon bond.

86. The compound according to any one of embodiments 69 to 84, whereinR₂ is selected from

wherein:W_(a) is selected from N and CQ₁;W_(b) is selected from N and CQ_(z);W_(e) is selected from N and CQ₃;W_(d) is selected from N and CQ₄;W_(e) is selected from N and CQ₅;Each of W_(a), W_(b), W_(c), W_(d), and W_(e) may be the same ordifferent from each other;Q₁, Q₂, Q₄, Q₅ are each independently selected from hydrogen, —OH, —NH₂,halogen, —CF₃, —CN, —Ac, alkyl(C₁-C₃), alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂(C₁-C₃), which may be optionally substituted with groups independentlyselected from F, Cl, Br, —OH, —NH₂, —OMe, —OEt, —NHMe, —SMe, —S(O)Me,-Me, and -Et;Q₃ is selected from —OH, —NH₂, F, Cl, alkyl(C₁-C₃), alkoxy(C₁-C₃),—S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃),—N(Alkyl)₂ (C₁-C₃), which may be optionally substituted with groupsindependently selected from F, Cl, —OH, —NH₂, —OMe, —OEt, -Me, and -Et.

87. The compound according to any one of embodiments 69 to 84, whereinR₂ is selected from

88. The compound according to any one of embodiments 69 to 84, whereinR₁ is selected from a 3, 4-, 5-, or 6-membered carbocycle orheterocycle.

89. The compound according to embodiment 87, wherein R₁ is an optionallysubstituted phenyl.

90. The compound according to any one of embodiments 68 to 83, whereinR₁ is optionally substituted with hydrogen, —OH, —NH₂, halogen, —CF₃,—CN, —Ac, Alkyl(C₁-C₃), Alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —SAlkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂(C₁-C₃), any of which may be optionally substituted.

91. The compound according to any one of embodiments 69 to 84, whereinR₃ is selected from hydrogen, —CN, —NH₂, amino (such as —NHMe, —NHethyl,—NHcyclopropyl, —NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), amido(such as —NHAc, —NHC(O)Et, —NHC(O)Pr, —NHC(O)phenyl, —C(O)NHMe,—C(O)NH₂, —C(O)NHEt, —C(O)NMe₂), sulfone, Sulfoxide, sulfonamide (suchas —SO₂NH₂, —NHSO₂Me), carbocycle (phenyl, cyclopropyl, cyclobutyl,cyclopentyl), or heterocycle, any of which may be optionallysubstituted.

92. The compound according to any one of embodiments 69 to 84, whereinR₃ is selected from hydrogen, —NH₂, amino (such as —NHMe, —NHEt,—NHcyclopropyl, —NHPh, —NHBn, —NMe₂, —NHpyridyl, —NHcyclopentyl), and—NHheterocycle or heterocycle (such as,

any of which may be optionally substituted with groups independentlyselected from hydrogen, alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, carbonate, amino, amide, andhalogen.

93. The compound according to any one of embodiments 69 to 84, whereinR₃, R₄, and R₅ may be optionally substituted with groups independentlyselected from hydrogen, alkyl, —OH, —NH₂, thioalkyl, alkoxy, ketone,ester, carboxylic acid, urea, carbamate, carbonate, amino, amide, andhalogen.

94. The compound according to any one of embodiments 69 to 84, whereinR₃ and R₄ may be connected to form an optionally substituted 5-, 6-, or7-membered carbocycle or heterocycle such as

95. The compound according to any one of embodiments 69 to 84, whereinR₄ is hydrogen.

96. The compound according to any one of embodiments 69 to 84, wherein Xis oxygen.

97. The compound according to any one of embodiments 69 to 84, whereinn=0, meaning B is absent.

98. The compound according to any one of embodiments 69 to 84, wherein Bis selected from —(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, where n is 0 or 1,meaning if n=0 then B is absent.

99. The compound according to any one of embodiments 69 to 84, wherein Ais selected from C═O and —CR_(x)R_(y)—.

100. The compound according to any one of embodiments 69 to 84, whereinthe compound of Formula IV is selected from:

-   3-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile    (Example 15)-   4-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile    (Example 16);-   N-(3-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)phenyl)acetamide    (Example 17);-   2-Benzyl-6-((3,4,5-trimethoxyphenyl)amino)pyridazin-3(2H)-one    (Example 54);-   2-Benzyl-6-((3,4-dimethoxyphenyl)amino)pyridazin-3(2H)-one (Example    60);-   N-(4-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)phenyl)acetamide    (Example 82);-   2-Benzyl-6-(4-hydroxy-3-methoxyphenyl)pyridazin-3(2H)-one (Example    83);-   2-Benzyl-6-((5,6-dimethoxypyridin-2-yl)amino)pyridazin-3(2H)-one    (Example 99);-   2-Benzyl-6-(3,4-dimethoxyphenoxy)pyridazin-3(2H)-one (Example 100);-   2-(4-(Methylsulfonyl)benzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 116);-   2-(4-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 117);-   2-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile    (Example 118);-   2-(3-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 119);-   2-(4-(tert-Butyl)benzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one    (Example 120);-   2-Benzyl-4-(2-hydroxy-3,4-dimethoxyphenyl)phthalazin-1(2H)-one    (Example 164);-   2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)-2H-phthalazin-1-one (Example    165);-   2-Benzyl-4-(3,4,5-trimethoxyphenylamino)-2H-phthalazin-1-one    (Example 171);-   2-Benzyl-4-(2,3,4-trimethoxyphenyl)phthalazin-1(2H)-one (Example    177);-   6-(4-hydroxyphenyl)-2-(1-phenylethyl)pyridazin-3(2H)-one (Example    178); and-   2-benzyl-6-(4-methyl-3-oxopiperazin-1-yl)pyridazin-3(2H)-one    (Example 179).

101. A pharmaceutical composition comprising a compound according to anyone of embodiments 1 to 99.

102. A compound according to any one of embodiments 1 to 100 for use asa medicament.

103. A method for inhibiting BET proteins in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto any one of embodiments 1 to 100.

104. A method for treating a disease that is sensitive to a BETinhibitor comprising administering a therapeutically effective amount ofa compound according to any one of embodiments 1 to 100.

105. A method for treating an autoimmune disease in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto any one of embodiments 1 to 100.

106. The method of embodiment 105, wherein the autoimmune disease isselected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia,Allergic Disease, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis,Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmunehepatitis, Autoimmune inner ear disease, Autoimmune myocarditis,Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmunethrombocytopenic purpura, Behcet's Disease, Bullous pemphigoid,Castleman's Disease, Celiac Disease, Churg-Strauss syndrome, Crohn'sDisease, Cogan's syndrome, Dry eye syndrome, Essential mixedcryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis,Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giantcell arteritis, Glomerulonephritis, Goodpasture's syndrome,Granulomatosis with Polyangiitis (Wegener's), Graves' Disease,Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia,Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, TypeI diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclasticvasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis,Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis,Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliarycirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum,Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis,Scleroderma, Sjogren's syndrome, Takayasu's arteritis, Transversemyelitis, Ulcerative colitis, Uveitis, and Vitiligo.

107. A method for treating inflammatory diseases or disorders in amammal comprising administering a therapeutically effective amount of acompound according to any one of embodiments 1 to 100.

108. The method of embodiment 107 wherein the inflammatory disease ordisorder is selected from sinusitis, pneumonitis, osteomyelitis,gastritis, enteritis, gingivitis, appendicitis, irritable bowelsyndrome, tissue graft rejection, chronic obstructive pulmonary disease(COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis,osteoarthritis, acute gout, acute lung injury, acute renal failure,burns, Herxheimer reaction, and SIRS associated with viral infections.

109. A method for treating or preventing a cancer in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto any one of embodiments 1 to 100.

110. The method of embodiment 109 wherein the cancer is a midlinecarcinoma.

111. The method of embodiment 109 wherein the cancer exhibitsoverexpression, translocation, amplification, or rearrangement of a mycfamily oncoproteins.

112. The method of embodiment 109 wherein the cancer is characterized byoverexpression of c-myc.

113. The method of embodiment 109 wherein the cancer is characterized byis characterized by overexpression n-myc.

114. The method of embodiment 109 wherein the cancer results fromaberrant regulation of BET proteins.

115. The method of embodiment 109 wherein the cancer is characterized byrecruitment of pTEFb to regulate oncogenes.

116. The method of embodiment 109 wherein the cancer is characterized byupregulation of CDK6, Bcl2, TYRO3, MYB and/or hTERT.

117. The method of embodiment 109 wherein the cancer is selected from:B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large celllymphoma, multiple myeloma, primary plasma cell leukemia, atypicalcarcinoid lung cancer, bladder cancer, breast cancer, cervix cancer,colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma,large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodularmelanoma, neuroblastoma, oesophageal squamous cell carcinoma,osteosarcoma, ovarian cancer, prostate cancer, renal clear cellcarcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma,NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer,esophageal cancer and head and neck squamous cell carcinoma, chroniclymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphomawith germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma,follicular lymphomas, activated anaplastic large cell lymphoma, primaryneuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma,T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer,Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, chroniclymphocytic leukemia, and mantle cell lymphoma.

118. The method of any one of embodiments 109 to 117 wherein thecompound of Formula I is administered in combination with anotheranticancer agent.

119. The method of embodiment 118, wherein the anticancer agent isselected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib),AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate,Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin,Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT(GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin),Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib(STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana),IFNa₂a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide),Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412(Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone(Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib(INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274,Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat(SAHA), and WP1130 (Degrasyn).

120. A method of treating a cardiovascular disease comprisingadministering a therapeutically effective amount of a compound accordingto any one of embodiments 1 to 100.

121. The method of embodiment 120, wherein the cardiovascular disease isdyslipidemia, atherosclerosis, hypercholesterolemia, or metabolicsyndrome.

122. A method of treating insulin resistance diabetes comprisingadministering a therapeutically effective amount of a compound accordingto any one of embodiments 1 to 100.

123. A method of treating a neurological disorder comprisingadministering a therapeutically effective amount of a compound accordingto any one of embodiments 1 to 100.

124. The method of embodiment 123 wherein the neurological disorder isAlzheimer's disease, Parkinson's disease, Huntington disease, bipolardisorder, schizophrenia, Rubinstein-Taybi syndrome, or epilepsy.

125. A method of male contraception comprising administering atherapeutically effective amount of a compound according to any one ofembodiments 1 to 100.

126. A method of treating HIV comprising administering a therapeuticallyeffective amount of a compound according to any one of embodiments 1 to100.

127. A method of treating a cancer associated with a viral infectioncomprising administering a therapeutically effective amount of acompound according to any one of embodiments 1 to 100.

128. The method of embodiment 127 wherein the virus is selected fromEpstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi'ssarcoma associated virus, human papilloma virus, Merkel cellpolyomavirus, and human cytomegalovirus.

129. The compound of embodiment 1, wherein the compound of formula I is1-(4-chlorobenzyl)-5-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyridin-2(1H)-one(Example 197).

Other embodiments of the present disclosure will be apparent to thoseskilled in the art from consideration of the specification and practiceof the present disclosure disclosed herein. It is intended that thespecification and examples be considered as exemplary only, with a truescope and spirit of the present disclosure being indicated by thefollowing claims.

What is claimed is:
 1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: W₁ is selected from N and CR₅; W₂ is selectedfrom N and CR₄; W₃ is selected from N and CR₃; each W may be the same ordifferent from each other; R₁ is selected from a carbocycles orheterocycles; R₂ is selected from a 5- or 6-membered monocycliccarbocycle or a 5- or 6-membered monocyclic heterocycle; R₃, R₄, and R₅are each independently selected from hydrogen, alkyl, —OH, —NH₂,thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate,carbonate, amino, amide, halogen, carbocycle, heterocycle, sulfone,sulfoxide, sulfide, sulfonamide, and —CN; R₃ and R₄ may be connected toform an optionally substituted 5-, 6-, or 7-membered carbocycle orheterocycle; R₄ may be connected to B or R₂ to form a carbocycle orheterocycle; X is selected from O and S; A is selected from—CR_(x)R_(y)—, C═O, —C(O)CR_(x)R_(y)—, —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—,—CR_(x)R_(y)CR_(z)R_(v)O—, —CR_(x)R_(y)CR_(z)R_(v)N—,—CR_(x)R_(y)CR_(z)R_(v)S—, and —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—;R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each independentlyselected from hydrogen, alkyl(C₁-C₈), halogen, —OH, —CF₃, amino, alkoxy(C₁-C₃), carboxyl, —CN, sulfone, and sulfoxide, carbocycle, andheterocycle, or two substituents selected from R_(x), R_(y), R_(z),R_(v), R_(Q) and R_(R) may form an oxo or thio-oxo group, or twosubstituents selected from R_(x), R_(y), R_(z), R_(v), R_(S), and R_(R)may be connected in a 5- or 6-membered ring to form a bicycliccarbocycle or bicyclic heterocycle; B is selected from—(CR_(a)R_(b))_(n)—, —(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—,—CR_(a)R_(b)O—, —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—,—SCR_(a)R_(b)—, —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—,—CR_(a)R_(b)S(O)—, —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—; n isselected from 0 and 1, meaning if n=0 then B is absent and R₂ isconnected directly to the center ring; R_(a), R_(b), R_(c), and R_(d)are each independently selected from hydrogen, alkyl(C₁-C₃), andalkoxy(C₁-C₃).
 2. The compound according to claim 1, wherein thecompound is of Formula II:

or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydratethereof, wherein: W₁ is selected from N and CR₅; W₂ is selected from Nand CR₄; W₃ is selected from N and CR₃, with the proviso that if W₃ is Nthen neither R₅ nor R₄ is —OH; each W may be the same or different fromeach other; R₁ is a carbocycle or heterocycle; V is selected from a5-membered monocyclic carbocycle or monocyclic heterocycle, where theheterocycle is connected to the rest of the molecule via a carbon-carbonbond, with the proviso that V cannot be unsubstituted thiophene,cyclopentyl, cyclopentenyl, ribofuranosyl, or furan, R₃, R₄, and R₅ areeach independently selected from hydrogen, alkyl, —OH, —NH₂, thioalkyl,alkoxy, ketone, ester, carboxylic acid, urea, carbamate, carbonate,amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide,sulfide, sulfonamide, and —CN, R₃ and R₄ may be connected to form anoptionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;R₄ may be connected to B or V to form a carbocycle or heterocycle; X isselected from O and S; A is selected from —CR_(x)R_(y)—, C═O,—C(O)CR_(x)R_(y)—, —CR_(x)R_(y)CR_(z)R_(y)—, —SO₂—,—CR_(x)R_(y)CR_(z)R_(v)O—, —CR_(x)R_(y)CR_(z)R_(v)N—,—CR_(x)R_(y)CR_(z)R_(v)S—, and —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—, withthe proviso that R_(x) and R_(y) cannot both be an unsubstituted phenylring, and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then R₄is not —OH, and with the proviso that if A is —CH₂CH₂O— or —CH₂C(O)NH—then V is not a substituted

 or a substituted

and with the proviso that if A is —CH₂CH₂O— then R₁ is not

R_(x), R_(y), R_(z), R_(v), R_(Q) and R_(R) are each independentlyselected from hydrogen, alkyl(C₁-C₈), halogen, —OH, —CF₃, amino, alkoxy(C₁-C₈), carboxyl, —CN, sulfone, sulfoxide, carbocycle, and heterocycle,or two substituents selected from R_(x), R_(y), R_(z), R_(v), R_(Q) andR_(R) may form an oxo or thio-oxo group, or two substituents selectedfrom R_(x), R_(y), R_(z), R_(v), R₅, and R_(R) may be connected in a 5-or 6-membered ring to form a bicyclic carbocycle or bicyclicheterocycle; B is selected from —(CR_(a)R_(b))_(n)—,—(CR_(a)R_(b)CR_(c)R_(d))—, —O—, —OCR_(a)R_(b)—, —CR_(a)R_(b)O—, —NH—,—NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—, —S—, —SCR_(a)R_(b)—, —CR_(a)R_(b)S—,—S(O)—, —S(O)CR_(a)R_(b)—, —CR_(a)R_(b)S(O)—, —SO₂—, —SO₂CR_(a)R_(b)—,and —CR_(a)R_(b)SO₂—; n is selected from 0 and 1, meaning if n=0 then Bis absent; and wherein R_(a), R_(b), R_(c), and R_(d) are eachindependently selected from hydrogen, alkyl(C₁-C₃), and alkoxy(C₁-C₃).3. The compound according to claim 1, wherein V is selected from anoptionally substituted 5-membered monocyclic heterocycle selected from


4. The compound according to claim 2, wherein V is optionallysubstituted with hydrogen, alkyl (C₁-C₄)(such as methyl, ethyl, propyl,isopropyl, butyl), alkoxy(C₁-C₄) (such as methoxy, ethoxy, isopropoxy),amino (such as —NH₂, —NHMe, —NHEt, —NHiPr, —NHBu —NMe₂, NMeEt, —NEt₂,—NEtBu), —NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as—NHC(O)Me, —NHC(O)Et, —C(O)NHMe, —C(O)NEt₂, —C(O)NiPr), —CF₃, CN, —N₃,ketone (C₁-C₄) (such as acetyl, —C(O)Et, —C(O)Pr), —S(O)Alkyl(C₁-C₄)(such as —S(O)Me, —S(O)Et), —SO₂alkyl(C₁-C₄) (such as —SO₂Me, —SO₂Et,—SO₂Pr), -thioalkyl(C₁-C₄) (such as —SMe, —SEt, —SPr, —SBu), carboxyl(such as —COOH), ester (such as —C(O)OMe, —C(O)OEt, —C(O)OBu), each ofwhich may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH₂,—NHMe, —OMe, —SMe, oxo, and thio-oxo.
 5. The compound according to claim2, wherein V is selected from an optionally substituted 5-memberedmonocyclic heterocycle containing one oxygen and one or two nitrogens,where the heterocycle is connected to the rest of the molecule via acarbon-carbon bond.
 6. The compound according to claim 2, wherein V isan optionally substituted isoxazole.
 7. The compound according to claim2, wherein V is


8. The compound according to claim 2, wherein A is selected from C═O and—CR_(x)R_(y)—.
 9. The compound according to claim 2, wherein R₁ isselected from an optionally substituted 3-, 4-, 5-, and 6-memberedcarbocycle or heterocycle.
 10. The compound according to claim 9,wherein the carbocycle or heterocycle is selected from cyclopropyl,phenyl, pyridyl, thiophene, cyclobutyl, piperidine, piperazine,cyclopentyl, and cyclohexyl.
 11. The compound according to claim 9,wherein R₁ is selected from an optionally substituted 5- and 6-memberedcarbocycle or heterocycle.
 12. The compound according to claim 11,wherein the carbocycle or heterocycle is selected from phenyl, pyridyl,thiophene, and cyclopentyl.
 13. The compound according to claim 12,wherein R₁ is selected from an optionally substituted phenyl or pyridylring.
 14. The compound according to claim 2, wherein B is selected from—(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, —S(O)—, —SO₂—, where n is 0 or 1,meaning if n=0 then B is absent.
 15. The compound according to claim 2,wherein the compound of Formula 11 is selected from:6-(3,5-Dimethylisoxazol-4-yl)-2-phenethylpyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(pyridin-2-ylmethyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(pyrimidin-2-ylmethyl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(3-(trifluoromethyl)benzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyrazin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyrimidin-2(1H)-one;1-(4-((Dimethylamino)methyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-onehydrochloric acid;5-(3,5-Dimethylisoxazol-4-yl)-1-(piperidin-4-ylmethyl)pyridin-2(1H)-onehydrochloric acid;5-(3,5-Dimethylisoxazol-4-yl)-1-((3,5-dimethylisoxazol-4-yl)methyl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methylpyridin-2(1H)-one;4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzamide;2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(quinoxalin-6-ylmethyl)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one(Example 19);2-Benzyl-4-methyl-6-(5-methylisoxazol-4-yl)pyridazin-3(2H)-one;2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluorobenzyl)pyridazin-3(2H)-one;2-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;2-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)benzonitrile;2-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;2-(2-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(2-methylbenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methylbenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methylbenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluoro-5-methylbenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methoxybenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methoxybenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methylbenzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluorobenzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylpropyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(quinolin-8-ylmethyl)pyridin-2(1H)-one;1-(Cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(Cyclobutylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(3-(Difluoromethyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenoxyethyl)pyridin-2(1H)-one;1-((5-Chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(5-methylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(isoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(isothiazol-4-yl)pyridin-2(1H)-one;2-Benzyl-6-((3,5-dimethylisoxazol-4-yl)amino)pyridazin-3(2H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2(1H)-one;1-Benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methylpyridin-2(1H)-one;1-Benzyl-3-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzoyl)pyridin-2(1H)-one;1-(4-Chlorobenzoyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)pyridin-2(1H)-one;N-(1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one;3-Amino-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-3-(benzylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(methylamino)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(naphthalen-2-ylmethyl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methoxybenzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one;1-Benzyl-5-(thiazol-5-yl)pyridin-2(1H)-one;1-Benzyl-5-(5-methyl-1H-imidazol-4-yl)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)-4-methylpyridazin-3(2H)-one;2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one;2-Benzyl-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-4-methyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one;2-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;4-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)-N-methylbenzamide;2-(2,6-Difluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(2,4,6-trifluorobenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-fluorophenyl)ethyl)pyridazin-3(2H)-one;2-(2-Chloro-6-fluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(isoxazol-4-ylmethyl)pyridazin-3(2H)-one;5-(5-Amino-3-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-onetrifluoroacetic acid;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(quinolin-8-ylmethyl)pyridazin-3(2H)-one;1-(1-(2-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one;1-(1-(4-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenylpropan-2-yl)pyridin-2(1H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(thiophen-3-ylmethyl)pyridazin-3(2H)-one;(R)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;(S)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;(S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;(R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one;1-(1-(3-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-6-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-6-methylpyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methylbenzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methylbenzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethyl)benzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-fluorophenyl)ethyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;1-(3-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(2-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(4-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one;1-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;(S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;(R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;2-((5-(3,5-Dimethylisoxazol-4-O-2-oxopyridin-1(2H)-yl)methyl)benzonitrile;1-(2,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile;1-(2,4-Difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(4-Chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(2-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(4-Chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(3,4,5-trifluorobenzyl)pyridin-2(1H)-one;2-((1H-Benzo[d]imidazol-5-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;6-(3,5-Dimethylisoxazol-4-yl)-2-(3,4,5-trifluorobenzyl)pyridazin-3(2H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(methylsulfonyl)benzyl)pyridin-2(1H)-one;1-((1H-Benzo[d]imidazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-(3-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-((1H-Indazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-((1H-Indol-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-((4-Chlorophenyl)sulfonyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;5-(3-Amino-5-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one;3-Amino-1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-methylpiperazin-1-yl)pyridin-2(1H)-oneHydrochloride;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methoxypyridin-2(1H)-one;1-(3,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((4-fluorophenyl)amino)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3-fluorophenyl)amino)pyridin-2(1H)-one;1-Benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;1-(4-Chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3-methylisothiazol-4-yl)pyridin-2(1H)-one;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(piperazin-1-yl)pyridin-2(1H)-oneHydrochloride;5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methoxybenzyl)pyridin-2(1H)-one;5-(3,5-Dimethylisoxazol-4-yl)-1-(pyrimidin-2-ylmethyl)pyridin-2(1H)-one;2-Benzyl-4-(3,5-dimethylisoxazol-4-yl) isoquinolin-1(2H)-one;2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2H-phthalazin-1-one;6-Benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one;7-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one;2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one; and2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one.
 16. Acompound of Formula III:

or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydratethereof, wherein: W₂ is selected from N and CR₄, W₃ is selected from Nand CR₃, each W may be the same or different from each other; R₁ is acarbocycle or heterocycle, R₂ is selected from a 6-membered monocycliccarbocycle or monocyclic heterocycle, R₃, R₄, and R₅ are eachindependently selected from hydrogen, alkyl, —OH, —NH₂, thioalkyl,alkoxy, ketone, ester, carboxylic acid, urea, carbamate, carbonate,amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide,sulfide, sulfonamide, and —CN, with the proviso that R₄ is not —OH andR₅ is not —COON or -ester; R₃ and R₄ may be connected to form anoptionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;R₄ may be connected to B or R₂ to form a carbocycle or heterocycle; X isselected from O and S; A is selected from —CR_(x)R_(y)—, C═O,—C(O)CR_(x)R_(y)—, —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—,—CR_(x)R_(y)CR_(z)R_(v)O—, —CR_(x)R_(y)CR_(z)R_(v)N—,—CR_(x)R_(y)CR_(z)R_(v)S—, and —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—; withthe proviso that R_(x) and R_(y) cannot both be an unsubstituted phenylring, and with the proviso that if A is —CH₂CH₂CH₂— and W₃ is N then R₄is not —OH, and with the proviso that if A is —CH₂CH₂O— then R₁ is not

R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each independentlyselected from hydrogen, alkyl(C₁-C₈), halogen, —OH, —CF₃, amino, alkoxy(C₁-C₈), carboxyl, —CN, sulfone, sulfoxide, carbocycle, and heterocycle,or two substituents selected from R_(x), R_(y), R_(z), R_(v), R_(Q) andR_(R) may form an oxo or thio-oxo group, or two substituents selectedfrom R_(x), R_(y), R_(z), R_(v), R₅, and R₁ may be connected in a 5- or6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle; Bis selected from —(CR_(a)R_(b))_(n)—, —(CR_(a)R_(b)CR_(c)R_(d))—, —O—,—OCR_(a)R_(b)—, —CR_(a)R_(b)O—, —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—,—S—, —SCR_(a)R_(b)—, —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—,—CR_(a)R_(b)S(O)—, —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—; n isselected from 0 and 1, meaning if n=0 then B is absent; and R_(a),R_(b), R_(c), and R_(d) are each independently selected from hydrogen,alkyl(C₁-C₃), and alkoxy(C₁-C₃).
 17. The compound according to claim 16,wherein R₂ is selected from an optionally substituted 6-memberedmonocyclic carbocycle (such as phenyl) or heterocycle (such as pyridyl,pyrimidine, pyrazine, and triazine), where the heterocycle is connectedto the rest of the molecule via a carbon-carbon bond.
 18. The compoundaccording to claim 16, wherein R₂ is selected from

wherein: W_(a) is selected from N and CQ₁; W_(b) is selected from N andCQ₂; W_(c) is selected from N and CQ₃; W_(d) is selected from N and CQ₄;W_(e) is selected from N and CO₅; Each W may be the same or differentfrom each other; Q₁, Q₂, Q₄, Q₅ are each independently selected fromhydrogen, —OH, —NH₂, halogen, —CF₃, —CN, —Ac, alkyl(C₁-C₃),alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃),—NHAlkyl(C₁-C₃), —N(Alkyl)₂ (C₁-C₃), which may be optionally substitutedwith groups independently selected from F, Cl, Br, —OH, —NH₂, —OMe,—OEt, —NHMe, —SMe, —S(O)Me, -Me, and -Et; Q₃ is selected from —OH, —NH₂,F, Cl, alkyl(C₁-C₃), alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃),—Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂ (C₁-C₃), which may beoptionally substituted with groups independently selected from F, Cl,—OH, —NH₂, —OMe, —OEt, -Me, and -Et.
 19. The compound according to claim16, wherein R₂ is selected from


20. The compound according to claim 16, wherein R₁ is selected from a 3,4-, 5-, or 6-membered carbocycle or heterocycle.
 21. The compoundaccording to claim 19, wherein R₁ is selected from an optionallysubstituted phenyl.
 22. The compound according to claim 16, wherein R₁is optionally substituted with hydrogen, —OH, —NH₂, halogen, —CF₃, —CN,—Ac, Alkyl(C₁-C₃), Alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃),—SAlkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂ (C₁-C₃), any of whichmay be optionally substituted.
 23. The compound according to claim 16,wherein B is selected from —(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, where nis 0 or 1, meaning if n=0 then B is absent.
 24. The compound accordingto claim 16, wherein A is selected from C═O and —CR_(x)R_(y)—.
 25. Thecompound according to claim 16, wherein the compound of Formula III isselected from: 1-Benzyl-5-(3,4,5-trimethoxyphenyl)pyridin-2(1H)-one;2-((2-Oxo-5-(3,4,5-trimethoxyphenyl)pyridin-1(2H)-yl)methyl)benzonitrile;1-Benzyl-2′-hydroxy-[3,4′-bipyridin]-6(1H)-one;1-Benzyl-5-((3,4-dimethoxyphenyl)amino)pyridin-2(1H)-one;2-Benzyl-4-(3,4-dimethoxyphenyl)isoquinolin-1(2H)-one;2-Benzyl-4-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one;2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)isoquinolin-1(2H)-one; and2-Benzyl-4-((3,4,5-trimethoxyphenyl)amino)isoquinolin-1(2H)-one.
 26. Acompound of Formula IV:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: W₂ is selected from N and CR₄, W₃ is selectedfrom N and CR₃, each W may be the same or different from each other; R₁is a carbocycle or heterocycle, R₂ is selected from a 6-memberedmonocyclic carbocycle or monocyclic heterocycle, R₃ and R₄ are eachindependently selected from hydrogen, alkyl, —OH, —NH₂, thioalkyl,alkoxy, ketone, ester, carboxylic acid, urea, carbamate, carbonate,amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide,sulfide, sulfonamide, and —CN, with the proviso that R₄ is not —OH; R₃and R₄ may be connected to form an optionally substituted 5-, 6-, or7-membered carbocycle or heterocycle, with the proviso that R₃ and R₄are not connected to form

R₄ may be connected to B or R₂ to form a carbocycle or heterocycle; X isselected from O and S; A is selected from —CR_(x)R_(y)—, C═O,—C(O)CR_(x)R_(y)—, —CR_(x)R_(y)CR_(z)R_(v)—, —SO₂—,—CR_(x)R_(y)CR_(z)R_(v)O—, —CR_(x)R_(y)CR_(z)R_(v)N—,—CR_(x)R_(y)CR_(z)R_(v)S—, and —CR_(x)R_(y)CR_(z)R_(v)CR_(Q)R_(R)—; withthe proviso that if A is C═O, then R₂ is not an optionally substituted

 where T is halogen, and with the proviso that R_(x) and R_(y) cannotboth be an unsubstituted phenyl ring, and with the proviso that if A is—CH₂CH₂CH₂— and W₃ is N then R₄ is not —OH, and with the proviso that ifA is —CH₂CH₂O— then R₁ is not

R_(x), R_(y), R_(z), R_(v), R_(Q), and R_(R) are each independentlyselected from hydrogen, alkyl(C₁-C₈), halogen, —OH, —CF₃, amino, alkoxy(C₁-C₈), carboxyl, —CN, sulfone, sulfoxide, carbocycle, and heterocycle,or two substituents selected from R_(x), R_(y), R_(z), R_(y), R_(Q) andR_(R) may form an oxo or thio-oxo group, or two substituents selectedfrom R_(x), R_(y), R_(z), R_(v), R₅, and R₁ may be connected in a 5- or6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle; Bis selected from —(CR_(a)R_(b))_(n)—, —(CR_(a)R_(b)CR_(c)R_(d))—, —O—,—OCR_(a)R_(b)—, —CR_(a)R_(b)—, —NH—, —NHCR_(a)R_(b)—, —CR_(a)R_(b)NH—,—S—, —SCR_(a)R_(b)—, —CR_(a)R_(b)S—, —S(O)—, —S(O)CR_(a)R_(b)—,—CR_(a)R_(b)S(O)—, —SO₂—, —SO₂CR_(a)R_(b)—, and —CR_(a)R_(b)SO₂—; n isselected from 0 and 1, meaning if n=0 then B is absent; R_(a), R_(b),R_(c), and R_(d) are each independently selected from hydrogen,alkyl(C₁-C₃), and alkoxy(C₁-C₃).
 27. The compound according to claim 26,wherein R₂ is selected from an optionally substituted 6-memberedmonocyclic carbocycle (such as phenyl) or heterocycle (such as pyridyl,pyrimidine, pyrazine, and triazine), where the heterocycle is connectedto the rest of the molecule via a carbon-carbon bond.
 28. The compoundaccording to claim 26, wherein R₂ is selected from

wherein: W_(a) is selected from N and CQ₁; W_(b) is selected from N andCQ₂; W_(c) is selected from N and CQ₃; W_(d) is selected from N and CQ₄;W_(e) is selected from N and CQ₅; Each of W_(a), W_(b), W_(c), W_(d),and W_(e) may be the same or different from each other; Q₁, Q₂, Q₄, Q₅are each independently selected from hydrogen, —OH, —NH₂, halogen, —CF₃,—CN, —Ac, alkyl(C₁-C₃), alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃),—SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂(C₁-C₃), which may be optionally substituted with groups independentlyselected from F, Cl, Br, —OH, —NH₂, —OMe, —OEt, —NHMe, —SMe, —S(O)Me,-Me, and -Et; Q₃ is selected from —OH, —NH₂, F, Cl, alkyl(C₁-C₃),alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃), —Salkyl(C₁-C₃),—NHAlkyl(C₁-C₃), —N(Alkyl)₂ (C₁-C₃), which may be optionally substitutedwith groups independently selected from F, Cl, —OH, —NH₂, —OMe, —OEt,-Me, and -Et.
 29. The compound according to claim 26, wherein R₂ isselected from


30. The compound according to claim 26, wherein R₁ is selected from a 3,4-, 5-, or 6-membered carbocycle or heterocycle.
 31. The compoundaccording to claim 39, wherein R₁ is an optionally substituted phenyl.32. The compound according to claim 26, wherein R₁ is optionallysubstituted with hydrogen, —OH, —NH₂, halogen, —CF₃, —CN, —Ac,Alkyl(C₁-C₃), Alkoxy(C₁-C₃), —S(O)Alkyl(C₁-C₃), —SO₂Alkyl(C₁-C₃),—SAlkyl(C₁-C₃), —NHAlkyl(C₁-C₃), and —N(Alkyl)₂ (C₁-C₃), any of whichmay be optionally substituted.
 33. The compound according to claim 26,wherein B is selected from —(CR_(a)R_(b))_(n)—, —O—, —NH—, —S—, where nis 0 or 1, meaning if n=0 then B is absent.
 34. The compound accordingto claim 26, wherein A is selected from C═O and —CR_(x)R_(y)—.
 35. Thecompound according claim 26, wherein the compound of Formula IV isselected from:3-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile;4-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile;N-(3-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)phenyl)acetamide;2-Benzyl-6-((3,4,5-trimethoxyphenyl)amino)pyridazin-3(2H)-one;2-Benzyl-6-((3,4-dimethoxyphenyl)amino)pyridazin-3(2H)-one;N-(4-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)phenyl)acetamide;2-Benzyl-6-(4-hydroxy-3-methoxyphenyl)pyridazin-3(2H)-one;2-Benzyl-6-((5,6-dimethoxypyridin-2-yl)amino)pyridazin-3(2H)-one;2-Benzyl-6-(3,4-dimethoxyphenoxy)pyridazin-3(2H)-one;2-(4-(Methylsulfonyl)benzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one;2-(4-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one;2-((6-Oxo-3-(3,4,5-trimethoxyphenyl)pyridazin-1(6H)-yl)methyl)benzonitrile;2-(3-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one;2-(4-(tert-Butyl)benzyl)-6-(3,4,5-trimethoxyphenyl)pyridazin-3(2H)-one;2-Benzyl-4-(2-hydroxy-3,4-dimethoxyphenyl)phthalazin-1(2H)-one;2-Benzyl-4-(4-hydroxy-3-methoxyphenyl)-2H-phthalazin-1-one;2-Benzyl-4-(3,4,5-trimethoxyphenylamino)-2H-phthalazin-1-one; and2-Benzyl-4-(2,3,4-trimethoxyphenyl)phthalazin-1(2H)-one.
 36. Apharmaceutical composition comprising a compound according claim
 1. 37.A method for inhibiting BET proteins in a mammal, treating an autoimmunedisease in a mammal, treating inflammatory diseases or disorders in amammal, or treating or preventing a cancer in a mammal, comprisingadministering a therapeutically effective amount of a compound accordingto claim
 1. 38. The method of claim 37, wherein the autoimmune diseaseis selected from Acute Disseminated Encephalomyelitis,Agammaglobulinemia, Allergic Disease, Ankylosing spondylitis,Anti-GBM/Anti-TBM nephritis, Anti-phospholipid syndrome, Autoimmuneaplastic anemia, Autoimmune hepatitis, Autoimmune inner ear disease,Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy,Autoimmune thrombocytopenic purpura, Behcet's Disease, Bullouspemphigoid, Castleman's Disease, Celiac Disease, Churg-Strauss syndrome,Crohn's Disease, Cogan's syndrome, Dry eye syndrome, Essential mixedcryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis,Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giantcell arteritis, Glomerulonephritis, Goodpasture's syndrome,Granulomatosis with Polyangiitis (Wegener's), Graves' Disease,Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia,Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, TypeI diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclasticvasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis,Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis,Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliarycirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum,Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis,Scleroderma, Sjogren's syndrome, Takayasu's arteritis, Transversemyelitis, Ulcerative colitis, Uveitis, and Vitiligo.
 39. The method ofclaim 37 wherein the inflammatory disease or disorder is selected fromsinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis,appendicitis, irritable bowel syndrome, tissue graft rejection, chronicobstructive pulmonary disease (COPD), septic shock, toxic shocksyndrome, SIRS, bacterial sepsis, osteoarthritis, acute gout, acute lunginjury, acute renal failure, burns, Herxheimer reaction, and SIRSassociated with viral infections.
 40. The method of claim 37 wherein thecancer is a midline carcinoma, exhibits overexpression, translocation,amplification, or rearrangement of a myc family oncoproteins, ischaracterized by overexpression of c-myc or n-myc, recruitment of pTEFbto regulate oncogenes, or upregulation of CDK6, Bcl2, TYRO3, MYB and/orhTERT, or results from aberrant regulation of BET proteins.
 41. Themethod of claim 37 wherein the cancer is selected from: B-acutelymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma,multiple myeloma, primary plasma cell leukemia, atypical carcinoid lungcancer, bladder cancer, breast cancer, cervix cancer, colon cancer,gastric cancer, glioblastoma, hepatocellular carcinoma, large cellneuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma,neuroblastoma, oesophageal squamous cell carcinoma, osteosarcoma,ovarian cancer, prostate cancer, renal clear cell carcinoma,retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midlinecarcinoma, B-cell lymphoma, non-small cell lung cancer, esophagealcancer and head and neck squamous cell carcinoma, chronic lymphocyticleukemia, follicular lymphoma, diffuse large B cell lymphoma withgerminal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma,follicular lymphomas, activated anaplastic large cell lymphoma, primaryneuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma,T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer,Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, chroniclymphocytic leukemia, and mantle cell lymphoma.
 42. The method of claim37, wherein the compound of Formula I is administered in combinationwith another anticancer agent.
 43. The method of claim 42, wherein theanticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152(Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235,Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran),Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine(Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone,Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol(Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin,Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran),Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone),Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib),Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid(Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248(Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine(Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).
 44. A method fortreating a disease that is sensitive to a BET inhibitor, acardiovascular disease, insulin resistance diabetes, a neurologicaldisorder, HIV, or a cancer associated with a viral infection, or amethod of male contraception, comprising administering a therapeuticallyeffective amount of a compound according to claim
 1. 45. The method ofclaim 44, wherein the cardiovascular disease is dyslipidemia,atherosclerosis, hypercholesterolemia, or metabolic syndrome.
 46. Themethod of claim 44 wherein the neurological disorder is Alzheimer'sdisease, Parkinson's disease, Huntington disease, bipolar disorder,schizophrenia, Rubinstein-Taybi syndrome, or epilepsy.
 47. The method ofclaim 46 wherein the virus is selected from Epstein-Barr Virus,hepatitis B virus, hepatitis C virus, Kaposi's sarcoma associated virus,human papilloma virus, Merkel cell polyomavirus, and humancytomegalovirus.